U.S. patent application number 10/831416 was filed with the patent office on 2004-10-14 for compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery therof.
Invention is credited to Kirby, Kenneth B., Pettersson, Berno.
Application Number | 20040202709 10/831416 |
Document ID | / |
Family ID | 22230257 |
Filed Date | 2004-10-14 |
United States Patent
Application |
20040202709 |
Kind Code |
A1 |
Kirby, Kenneth B. ; et
al. |
October 14, 2004 |
Compositions for rapid and non-irritating transdermal delivery of
pharmaceutically active agents and methods for formulating such
compositions and delivery therof
Abstract
A transdermal delivery system (TDS)for use in treatment of
living bodies may be applied as an open (liquid, gel) or closed
(patch) article. The TDS is composed of a particular active agent
which dictates an associated selection of certain solvents, solvent
modifiers, solute modifiers and skin stabilizers with which the
medicament forms a true solution that rapidly crosses the skin
barrier. The associated selection of the particular solvents,
solvent modifiers, solute modifiers and skin stabilizers is based
on a balancing of the molecular properties of all the components
against the molecular properties of all the components plus the
particular active agent. The TDS may also include a source of
cellular energy to induce CAMP or cGMP. The TDS improves delivery
of active agents having a molecular weight greater than 340 Daltons
and increases dosage above 0.25 mg/day for such active agents.
Inventors: |
Kirby, Kenneth B.; (Lake
Park, FL) ; Pettersson, Berno; (Perry, GA) |
Correspondence
Address: |
MCHALE & SLAVIN, P.A.
2855 PGA BLVD
PALM BEACH GARDENS
FL
33410
US
|
Family ID: |
22230257 |
Appl. No.: |
10/831416 |
Filed: |
April 23, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10831416 |
Apr 23, 2004 |
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10074497 |
Feb 11, 2002 |
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10074497 |
Feb 11, 2002 |
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09381095 |
May 11, 2000 |
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6444234 |
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09381095 |
May 11, 2000 |
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PCT/US99/15297 |
Jul 7, 1999 |
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60091910 |
Jul 7, 1998 |
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Current U.S.
Class: |
424/449 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 36/74 20130101; Y10S 514/946 20130101; A61K 36/53 20130101;
A61K 36/324 20130101; Y10S 514/947 20130101; A61K 36/752 20130101;
A61K 36/232 20130101; A61K 36/74 20130101; A61K 36/752 20130101;
A61K 36/324 20130101; A61P 17/00 20180101; A61K 9/0014 20130101;
A61K 36/232 20130101; A61K 47/12 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 36/53 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/449 |
International
Class: |
A61K 009/70 |
Claims
What is claimed is:
1. A transdermal delivery system (TDS) for treatment of a living
body by rapidly delivering at least one active agent across the
skin, said TDS including an effective amount of at least one active
agent solute in a solvent, said solute having molecular properties
including van der Waals forces and dipole moments, said solvent
having molecular properties including van der Waals forces and
dipole moments, said molecular properties of said solvent being
substantially the same as said molecular properties of said solute
and said solute.
2. A TDS of claim 1 wherein said solvent comprises at least one
solvent modifier forming a solvent system, said solvent modifier
changing the polarity of said solvent system to substantially equal
the polarity of said solute, said solvent modifier having molecular
properties including van der Waals forces and dipole moments, said
solvent system having molecular properties including van der Waals
forces and dipole moments, said molecular properties of said
solvent system substantially the same as said molecular properties
of said solvent system and said solute.
3. A TDS of claim 1 wherein said-solvent includes at least one
solute modifier forming a solvent system, said solute modifier
forming a reversible complex with said solute for facilitating
passage of the solute complex across the skin, said solute modifier
having molecular properties including van der Waals forces and
dipole moments, said molecular properties of said solvent system
being substantially the same as said molecular properties of said
solvent system and said solute.
4. A TDS of claim 2 wherein said solvent system includes at least
one solute modifier, said solute modifier forming a reversible
complex with said solute for facilitating passage of the solute
complex across the skin, said solute modifier having molecular
properties including van der Waals forces and dipole moments, said
molecular properties of said solvent system being substantially the
same as said molecular properties of said solvent system and said
solute.
5. A TDS of claim 1 wherein said solvent includes at least one
compound for stimulating the release of cellular energy in the skin
forming a solvent system, said compound having molecular properties
including van der Waals forces and dipole moments, said solvent
system having molecular properties including van der Waals forces
and dipole moments, said molecular properties of said solvent
system being substantially the same as said molecular properties of
said solvent system and said solute.
6. A TDS of claim 5 wherein said compound for stimulating the
release of cellular energy generates cAMP at the cellular
level.
7. A TDS of claim 5 wherein said compound for stimulating the
release of cellular energy generates cGMP at the cellular
level.
8. A TDS of claim 2 wherein said solvent system includes at least
one compound for stimulating the release of cellular energy in the
skin, said compound having molecular properties including van der
Waals forces and dipole moments, said solvent system having
molecular properties, said molecular properties of said solvent
system being substantially the same as said molecular properties of
said solvent system and said solute.
9. A TDS of claim 3 wherein said solvent system includes at least
one compound for stimulating the release of cellular energy in the
skin, said compound having molecular properties including van der
Waals forces and dipole moments, said solvent system having
molecular properties including van der Waals forces and dipole
moments, said molecular properties of said solvent system being
substantially the same as said molecular properties of said solvent
system and said solute.
10. A TDS of claim 4 wherein said solvent system includes at least
one compound for stimulating the release of cellular energy in the
skin, said compound having molecular properties including van der
Waals forces and dipole moments, said molecular properties of said
solvent system being substantially the same as said molecular
properties of said solvent system and said solute.
11. A TDS of claim 1 wherein said solvent includes at least one
skin stabilizer composition to facilitate safe and effective dosage
of said active agent and protect from local and systemic
sensitization forming a solvent system, said composition having
molecular properties including van der Waals forces and dipole
moments, said solvent system having molecular properties including
van der Waals forces and dipole moments, said molecular properties
of said solvent system being substantially the same as said
molecular properties of said solvent system and said solute.
12. A TDS of claim 2 wherein said solvent system includes at least
one skin stabilizer composition to facilitate safe and effective
dosage of said active agent and protect from local and systemic
sensitization, said composition having molecular properties
including van der Waals forces and dipole moments, said molecular
properties of said solvent system substantially the same as said
molecular properties of said solvent system and said solute.
13. A TDS of claim 3 wherein said solvent system includes at least
one skin stabilizer composition to facilitate safe and effective
dosage of said active agent and protect from local and systemic
sensitization, said composition having molecular properties
including van der Waals forces and dipole moments, said molecular
properties of said solvent system substantially the same as said
molecular properties of said solvent system and said solute.
14. A TDS of claim 4 wherein said solvent system includes at least
one skin stabilizer composition to facilitate safe and effective
dosage of said active agent and protect from local and systemic
sensitization, said composition having molecular properties
including van der Waals forces and dipole moments, said molecular
properties of said solvent system substantially the same as said
molecular properties of said solvent system and said solute.
15. A TDS of claim 5 wherein said solvent system includes at least
one skin stabilizer composition to facilitate safe and effective
dosage of said active agent and protect from local and systemic
sensitization, said composition having molecular properties
including van der Walls forces and dipole moments, said molecular
properties of said solvent system substantially the same as said
molecular properties of said solvent system and said solute.
16. A TDS of claim 1 wherein said solvent includes at least one
membrane permeability modifier to enhance penetration of the skin
forming a solvent system, said membrane permeability modifier
having molecular properties including van der Waals forces and
dipole moments, said molecular properties of said solvent system
being substantially the same as said molecular properties of said
solvent system and said solute.
17. A TDS of claim 2 wherein said solvent system includes at least
one permeability modifier to enhance penetration of the skin, said
permeability modifier having molecular properties including van der
Waals forces and dipole moments, said molecular properties of said
solvent system substantially the same as said molecular properties
of said solvent system and said solute.
18. A TDS of claim 4 wherein said solvent system includes at least
one permeability modifier having molecular properties including van
der Waals forces and dipole moments, said molecular properties of
said solvent system substantially the same as said molecular
properties of said solvent system and said solute.
19. A TDS of claim 10 wherein said solvent system includes at least
one permeability modifier having molecular properties including van
der Waals forces and dipole moments, said molecular properties of
said solvent system substantially the same as said molecular
properties of said solvent system and said solute.
20. A TDS of claim 14 wherein said solvent system includes at least
one permeability modifier having molecular properties including van
der Waals forces and dipole moments, said molecular properties of
said solvent system substantially the same as said molecular
properties of said solvent system and said solute.
21. A TDS of claim 15 wherein said solvent system includes at least
one permeability modifier having molecular properties including van
der Waals forces and dipole moments, said molecular properties of
said solvent system substantially the same as said molecular
properties of said solvent system and said solute.
22. A TDS of claim 3 wherein said solvent system includes at least
one permeability modifier having molecular properties including van
der Waals forces and dipole moments, said molecular properties of
said solvent system substantially the same as said molecular
properties of said solvent system and said solute.
23. A TDS of claim 9 wherein said solvent system includes at least
one permeability modifier having molecular properties including van
der Waals forces and dipole moments, said molecular properties of
said solvent system substantially the same as said molecular
properties of said solvent system and said solute.
24. A TDS of claim 13 wherein said solvent system includes at least
one permeability modifier having molecular properties including van
der Waals forces and dipole moments, said molecular properties of
said solvent system substantially the same as said molecular
properties of said solvent system and said solute.
25. A TDS of claim 1 wherein said solvent includes a capillary
dilator forming a solvent system having molecular properties
including van der Waals forces and dipole moments, said molecular
properties of said solvent system substantially the same as said
molecular properties of said solvent system and said solute.
26. A TDS of claim 18 wherein said solvent system includes a
capillary dilator having molecular properties including van der
Waals forces and dipole moments, said molecular properties of said
solvent system substantially the same as said molecular properties
of said solvent system and said solute.
27. A TDS of claim 19 wherein said solvent system includes a
capillary dilator having molecular properties including van der
Waals forces and dipole moments, said molecular properties of said
solvent system substantially the same as said molecular properties
of said solvent system and said solute.
28. A TDS of claim 21 wherein said solvent system includes a
capillary dilator having molecular properties including van de
Waals forces and dipole moments, said molecular properties of said
solvent system substantially the same as said molecular properties
of said solvent system and said solute.
29. A TDS of claim 23 wherein said solvent system includes a
capillary dilator having molecular properties including van der
Waals forces and dipole moments, said molecular properties of said
solvent system being substantially the same as said molecular
properties of said solvent system and said solute.
30. A TDS of claim 24 wherein said solvent system includes a
capillary dilator having molecular properties including van der
Waals forces and dipole moments, said molecular properties of said
solvent system being substantially the same as said molecular
properties of said solvent system and said solute.
31. A transdermal delivery system (TDS) for treatment of a living
body by rapidly delivering an effective dose of at least 0.25
mg/cm2/day of at least one active agent across the skin by
application of said TDS to an area of the skin, said TDS comprising
said at least one active agent and a solvent system, said at least
one active agent having a molecular weight in excess of 300
Daltons, said at least one active agent having molecular properties
including van der Waals forces and dipole moments, said at least
one active agent dissolved in said solvent system as a solute, said
solvent system having molecular properties including van der Waals
forces and dipole moments, said molecular properties of said
solvent system substantially the same as said molecular properties
of said solvent system and said solute.
32. A TDS of claim 31 wherein said molecular weight of said active
agent is from about 340 Daltons to about 22,000 Daltons.
33. A TDS of claim 31 wherein said effective dose is from about
0.25 mg/cm2/day to about 1 mg/cm2/day.
34. A TDS of claim 33 wherein said molecular weight of said active
agent is from about 340 Daltons to about 22,000 Daltons.
35. A TDS of claim 31 wherein said TDS is formed as a unit dose,
said unit dose being approximately 1 cc, said unit dose comprising
from about 0.25 mg to about 1 mg of said medicament.
36. A TDS of claim 35 wherein said unit dose is a patch.
37. A TDS of claim 35 wherein said unit dose is a liquid.
38. A TDS of claim 31 wherein said molecular properties of said
solute and solvent system are within approximately .+-.20% of said
molecular properties of said solvent system.
39. A method of selecting the ingredients and amounts of a TDS
comprising the steps of: (a) selecting one or more active agents
necessary to treat a specific condition; (b) quantifying the amount
of said active agent for an effective dose; (c) quantifying the
molecular properties of said active agent to include van der Waals
forces and the sum of mol-moments; (d) surveying solvents for said
active agent; (e) quantifying the amounts of said solvents to
solubilize said active agent; (f) quantifying the molecular
properties of said solvents to include van der Waals forces and
mol-moments; (g) comparing the molecular properties of said
solvents to said molecular properties of said active agent; (h)
determining additional ingredients to form a solvent system for
transmigration; (i) quantifying the molecular properties of said
additional ingredients to include van der Waals forces and
mol-moments; (j) determining a weighted sum of said molecular
properties of said additional ingredients and said molecular
properties of said solvents to determine molecular properties of
said solvent system; (k) summing said molecular properties of said
solvent system and said active agent; (l) comparing (j) and (k);
and (m) selecting said solvent system wherein said molecular
properties of said active agent and said solvent system are
approximately .+-.20% of said molecular properties of said solvent
system.
Description
RELATED APPLICATIONS
[0001] This application is a division of Ser. No. 10/074,497, filed
Feb. 11, 2002 and now U.S. Pat. No.______, which is a division of
Ser. No. 09/381,095, filed May 11, 2000, now U.S. Pat. No.
6,444,234 issued Sep. 3, 2002 which is a sec. 371 application of
PCT/US/99/15297, filed Jul. 7, 1999 which claims priority to
Provisional Application 60/091,910, filed Jul. 7, 1998.
FILED OF THE INVENTION
[0002] This invention relates to transdermal delivery of active
agents, including pharmaceuticals, cosmetics, nutrients, and the
like, across the skin barrier of humans or other animals and to a
method for developing new transdermal delivery systems for any
particular polar or non-polar active agent of small or large
molecular size, which delivery systems are capable of rapidly
delivering the active agent to a targeted location systemically or
locally.
BACKGROUND OF THE INVENTION
[0003] The pharmaceutical industry is actively seeking to develop
new and improved modes of drug delivery to enhance the
effectiveness of particular drugs, including, targeting the drug to
the intended site, reducing dosage, decreasing toxicity, and the
like. Major efforts are underway in molecule stabilization for
parenteral applications, extended release modalities for enteral
drugs and photactivated chemotherapeutic molecules, for example.
Delivery of medications via transdermal drug delivery (TDD) systems
(patches) has also seen dramatic developments, see U.S. Pat. Nos.
4,879,275; 3,996,934; and 3,731,683. For example, it is now
generally agreed that chemical modification of the barrier
properties of the skin is a safe and effective method to enhance
penetration of medicaments (Ref. 1). However, to some extent it
seems that this mode of delivery has reached its technological
limits.
[0004] The present inventors have analyzed the TDD systems and have
been able to identify certain limiting factors. These include, for
example, limitations to compounds which are
[0005] lipophilic medicaments;
[0006] medicaments with an effective therapeutic dose of less than
1 mg per day;
[0007] medicaments having a melting point below about 150.degree.
C.;
[0008] medicaments having molecular weight of from less than about
300 to about 500 Daltons (the larger the molecule, the less is the
amount deliverable via the stratum corneum);
[0009] molecules which do not elicit a rapidly cascading immune
response when transmigrating the skin.
[0010] With regard to the molecular weight limitations, currently
commercially available TDD systems deliver molecules with molecular
weights less than about 340 D and in amounts generally less than
about 1.0 mg per 24 hours.
[0011] Additionally, candidate medicaments should also, preferably,
be soluble in ethanol and/or isopropanol and/or glycols or dimethyl
sulfoxide (DMSO) and should not be chemically altered by
solubilization. Another potentially limiting factor is for
compounds which can have efficacy at relatively small doses
introduced systemically via the capillary net of the dermis. Main
limiting factors thus include molecule size and irritation
potential of the medicament plus solvent(s) and other
components.
[0012] The inventors have also analyzed the chemistry and chemical
structures of active ingredients and carriers of transdermal
delivery systems and have found other limiting factors leading to
the limited success of transdermal drug delivery. Most typically it
has been observed that these systems have not been widely
acceptable because the drug carriers chemically bound with the
medicament resulting in non-bioavailable compounds transmigrating
the skin; or/and the carrier, e.g., DMSO, reduces the medicament
yielding a non-bioavailable or non-bio-equivalent compound or
creates toxic by-products of transmigration.
[0013] Only about 1% or less of known medicaments would not be
excluded for administration by a TDD system based on the above
limiting factors. Still further, TDD systems currently available
are usually subject to broadly varying results as a function of the
circulation efficiency of the patient. Age, size and weight of the
patient all impact how efficiently these systems perform. For most
TDD systems there is virtually no drug penetration for the first
hour after application and often 24 to 48 hours are required to
achieve a therapeutic level.
[0014] The anatomy and physiology of the integument was analyzed to
understand the complex protective mechanism of physical,
biochemical and bio-electrical gradients which work to minimize the
penetration of foreign substances and sensitize the organism to
react more rapidly and aggressively to future exposures. As a
result of this analysis it is postulated that:
[0015] The primary pathway of transdermally delivered drugs is
paracellular, i.e., around the cells, then through the elastin
glue.
[0016] The glue-like compound, elastin, composed of collagen and
hyaluronic acid and other lipids, which occupies the interstices
between the cells of the top-most layer of the skin (i.e., the
epidermis, including, e.g., stratum corneum (SC), lucidum,
granulosum, spinosus) must be dissolved (or otherwise disrupted) in
order for a medicament or other active agent, dissolved in a
solvent, to transmigrate through viable skin (VS) to the
subcutaneous tissues where the cutaneous plexi of the capillary net
can be reached and/or deeper penetration achieved (Ref. 2). When
the elastin is dissolved, other agents may then transmigrate the
outer layers, so the body immediately begins to attempt to repair
the damage caused by the dissolution.
[0017] Skin penetration enhances (SPE) which delipidize can reduce
the barrier capacity of the SC as a function of species of enhancer
and its concentration. Permeability may often be adjusted by
modifying the HLB of the enhancer (Ref. 3).
[0018] Capilary circulation acts as a sink for the medicament, thus
maintaining a steep chemical potential gradient across the skin
(Ref. 4).
[0019] Diffusivity of a drug molecule is dependent on properties of
both the medicament and the medium (carrier). The diffusivity in
liquid media, in general, tends to decrease with increased
molecular volume (Ref. 5).
[0020] The rate of skin penetration is a function of (1) the
Diffusion Coefficient, (2) the barrier partitioning tendencies, (3)
binding affinities, and (4) the rate of metabolism of the
medicament by the skin (Ref. 6). The Diffusion Coefficient of the
medicament is influenced by (1) molecular weight, (2) molecular
structure, (3) additives, (4) rate of metabolism of the medicament
by the skin. Diffusion is also dependent on the carrier, with
diffusivity decreasing with increased molecular volume.
[0021] An optimum HLB is required for a medicament to penetrate
efficiently. The optimum HLB may be predicted by plotting the log
(Permeability Coefficient)vs. Log (Oil and Water Partition
Coefficient) of the medicament for the SC and the VS (Ref. 4).
[0022] Highly lipophilic drugs bind readily in the VS and,
therefore, dissolution into the blood is minimal (Ref. 6).
Therefore, highly lipophilic drugs must be shielded to inhibit such
binding.
[0023] Skin metabolizes drugs effectively, so metabolism issues in
the skin, such as, enzyme saturation and/or inhibition,
medicament/metabolite fluxes (e.g., how rapidly and completely does
the drug metabolize to a different form) should be taken into
account.
[0024] Un-ionized species of medicaments transmigrate more readily
(Ref. 4). Generally, un-ionized species are two orders of magnitude
more permeable than their ionized form.
[0025] The Hilderbrand Solubility Parameter (HSP) is useful for
predicting the mutual solubility and compatibility of medicaments,
SPEs, and polymers and for optimizing skin permeability (Ref. 7).
The HSP describes that attractive forces between molecules and is
defined as the square root of the Cohesive Energy Density (Ref. 8).
The HSP spans a range where the low value is associated with
lipophilic compounds and a high value with hydrophilic compounds.
The solubility parameter can be further partitioned into polar,
non-polar, dispersive, and hydrogen bonding components which are
useful to predict molecular interactions between compounds (Ref.
9). The solubility parameter or Cohesive Energy Density is
synonymous with lipophilic/hydrophilic properties (Ref. 4). Dipole
moment is also an expression of the Cohesive Energy Density.
[0026] Transient increases in cutaneous blood flows may result in
increased systemic absorption of the drug from the depot of the TDD
(Ref. 5).
[0027] Furthermore, cellular biological issues were reviewed in
order to identify and categorize membrane and organelle functions,
both in the integument and in other tissues, which might be subject
to variations which might help or hinder tissue transmigration of a
medicament and solvent. In particular, it is proposed that,
[0028] SPE's and solvent modification systems can cause irritation
apart from the medicament they are delivering. Chronic exposure to
irritants has the potential to become carcinogenic and, therefore,
care must be taken in the design and testing of TDD systems.
[0029] Efferent tactile corpuscles of nerves form an "early warning
detection system." The cellular and humoral components of this
peripheral immune surveillance system present in the skin are
responsible for the genesis of a hapten-specific, cell-mediated
immune response following the penetration of the skin by, and
complexing of skin components with, sensitizing chemicals and drugs
(Ref. 10). If a drug is able to penetrate the skin and covalently
bind with amino acids in the skin, dermal hypersensitivity is
possible. If the hapten-protein conjugate is of sufficient size to
be recognized as a foreign antigen, a specific antibody or
cell-mediated immune response will ensue that sensitizes the skin's
immune system to the hapten molecule. Upon re-exposure of the skin
to the sensitizing chemical, a dermal hypersensitivity reaction of
the delayed onset type 4 hypersensitization may be elicited (Ref.
11). Effective transmigration must be able to elude or minimize
this response to effectuate repeated challenge without anaphylaxis
or ACD sensitization. Avoiding binding in the skin is, therefore,
an important objective.
[0030] Some SPE's reduce residence time of the medicament in the
skin and reduce the extent of cutaneous metabolism thereby reducing
exposure to the medicament or metabolite. The faster the medicament
moves, the less metabolism takes place. Rate and extent of
metabolism in the liver and skin on a unit basis are virtually the
same and disposition is the same by IV dosage (Ref. 12).
[0031] Virtually any solvent used to dissolve and form a medium for
drugs is toxic on the cellular level at the concentrations
required, therefore, the tissues are effectively challenged with
eliminating the medicament and the solvent, thereby draining
substantial energy from the system.
[0032] Most challenges force the cell to expend adenosine
triphosphate (ATP) to move compounds across gradients or to
maintain barrier integrity against transmigration by compounds.
[0033] Adenylate cyclase substrate for the cAMP system, when
varied, can yield substantial changes in a cell's tolerance for,
and ability to recover from, the challenge of dermal
transmigration, accelerating the time line to a steady,
bio-available equilibrium of the medicament (Ref. 13).
[0034] Topical, transdermal drug delivery modalities, nevertheless,
have certain apparent benefits so that there is still much activity
not only in the patch systems but also in the non-patch transdermal
delivery systems, such as gels, ointments, and other topical
formulations.
OBJECTS OF THE INVENTION
[0035] Accordingly, it is a primary object of the invention to
provide compositions for the rapid transdermal administration of
medicaments or other active agents to humans or other animals which
does not require use of a "patch" delivery system.
[0036] Another object of the invention is to provide compositions
effective for transdermal delivery of active compounds not
previously amenable to this route of administration, particularly
for pharmacological agents having molecular weights in excess of
about 300 D and/or at dosages in excess of 0.25 mg/cm.sup.2 per
day, especially, in excess of about 1 mg/cm.sup.2/day.
[0037] It is another object of the invention to provide topical
compositions for transdermal delivery of active agents for humans
and other animals which leaves the barrier properties of the skin
substantially intact and which invokes only minimal or
substantially no immune response at the site of application.
[0038] Still another object of the invention is to provide a
standardized solvent/carrier base system which is useful for
forming topically applied compositions for transdermal
administration of many different medicaments with none or only
minimal modification required to achieve a true solution of the
medicament and effective, safe, and rapid transmigration of the
medicament through intact skin.
[0039] Another object of the invention is to provide safe and
effective compositions for transdermal administration of a variety
of medicaments and other active agents of low or high molecular
weight which allows repetitive applications over short or long
periods of time at the same site on the intact skin without causing
damage to or immunological reaction by the skin.
[0040] It is another object of the invention to provide a method
for formulating safe and effective compositions for topical
transdermal application of an active agent by matching the
solvent/carrier system for the particular active agent which will
allow the agent to transmigrate across the skin barrier with no or
only minimal immunological response at the site of application and
without degrading the chemical structure or bioactivity of the
active agent.
[0041] These and other objects of the invention will become clearer
upon review of the following more detailed description and specific
embodiments, and with the aid of the accompanying drawings in
which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1 is a graphical representation of the results obtained
in Example 13, for the flux (.mu.g/cm.sup.2) vs. time (h), of
morphine (as morphine sulfate) under open (lotion) conditions using
the topical delivery system SDS-L;
[0043] FIG. 2 is a graphical representation similar to FIG. 1 but
for testing under closed (patch) conditions using the SDS-L
delivery system described in Example 13;
[0044] FIG. 3 is a graphical representation similar to FIG. 1 but
using the topical delivery system SDS-S, as described in Example
13;
[0045] FIG. 4 is graphical representation similar to FIG. 2 (closed
patch application) for transdermal delivery of morphine, but using
the topical delivery system SDS-S.
SUMMARY OF THE INVENTION
[0046] Based on the above observations and reviews of the overall
biological systems of the skin and vascular organs, including at
the cellular and microbiological levels, it was concluded that an
effective and "universal" transdermal drug delivery system (as used
herein, unless the context indicates otherwise, the reference to
"drug" delivery is intended to include not only drugs, medicines,
pharmacologicals, and other biologically active ingredients, but
also other active agents, such as, cosmetically active substances,
nutrient substances and the like) should have the following
characteristics and features:
[0047] ability to dissolve and emulsify the active agent down to
individual molecules (true solutions) in a carrier which remains
liquid long enough to penetrate the epidermis;
[0048] remains stable as formulated and not form an irreversible
complex with other substances;
[0049] does not damage the skin with repeated use;
[0050] releases the active agent appropriately and does not alter
the agent or leave as residual compounds which might be
sensitizing.
[0051] The present invention provides a topical formulation for the
transdermal delivery of an active agent which addresses the design
of the integument as a biologically responsive physical, chemical
and bioelectrical barrier against the active agent(s) and
solvent(s). Accordingly, solvent(s) and modifying component(s) are
selected so that permanent or strong covalent bonds with the
medicament or other active agent are not formed, while the
complexes that are formed facilitate movement of the complex past
the viable skin to its optimal targeted internal circulation system
of blood, lymph or neural, or beyond these systems, wherein the
complexers and modifiers are readily stripped from the active agent
at the intended site of application, thereby leaving the active
agent free to seek the appropriate receptors once released.
[0052] At the same time, the formulations according to this
invention are designed to modify the active agent and solvent(s) to
minimize their reactivity and sensitizing characteristics as well
as making the active agent more "slippery" thereby facilitating
transmigration through the skin. By facilitating the transmigration
and increasing the rate of diffusion of the active agent and other
system components through the skin the less time the formulation
will have to remain in the tissues and the lower the physiological
response. In part, this is accomplished by selecting solvent(s) and
modifier(s) to provide a true solution, namely a solution of the
various components in the solvent system on a molecular level,
while at the same time forming a protective "coating" or temporary
complex with the active agent to facilitate its intact
transmigration through the skin.
[0053] The present invention also provides transdermal drug
delivery systems which may include a substance which can assist the
skin in repairing damage which is caused by the transmigration of
the delivery system.
[0054] In one broad aspect of the invention there is provided a
topical formulation for rapid transdermal delivery of an active
agent through intact skin wherein the formulation includes (1)
active agent, (2) solvent system in which the active agent is
soluble, and (3) a substance capable of in vivo stimulation of
adenosine 3',5'-cyclic monophosphate (cAMP) or cyclic guanosine
3',5'-monophosphate (cGMP).
[0055] The substance capable of in vivo cAMP stimulation is,
preferably, an extract of Coleus Forskholi, especially a labdane
diterpene, such as Forskolin, or colforsin or coleonol.
[0056] The formulation may and, preferably will, also include one
or more additional ingredients effective for enhancing percutaneous
absorption of the active agent in its intact, bioactive form. Such
additional agents include, for example, one or more of modifiers
for the active agent (solute) and/or solvents, such as,
methylsulfonylmethane, terpene compounds, skin penetration
enhancers, glycerylmonolaurate, quaternium cationic sufactants,
N,N-dialkyl alkanolamines, such as N,N-diethylethanolamine,
steroids, such as dehydroepiandosterone, oily substances, such as
eicosapentanoic acid, vitamins, such as A, D.sub.3, E, K.sub.1.
[0057] According to a particular embodiment of the invention the
topical, liquid, composition is effective for transdermal delivery
of high molecular weight active agent (solute), especially
medicaments and other active agents having molecular weights of at
least about 350 Daltons (350 D), at delivery rates of greater than
about 0.25 milligrams (mg) per square centimeter (cm.sup.2) per 24
hours. According to this embodiment, the composition may be
formulated as a unit dosage (e.g. one cubic centimeter (1 cc)
containing from about 0.25 to about 1.5 mg of active agent having
molecular weight of at least about 350 D in a carrier in which the
active agent is completely dissolved. The carrier includes a
solvent system in which the active agent is at least substantially
soluble, at least one solvent modifying compound to facilitate
transdermal delivery of the active agent and, as necessary, to
increase solubility of active agent in the solvent system; and at
least one solute (active agent) modifying compound forming a
non-covalently bonded complex with the solute. In this embodiment,
too, addition of a substance, e.g., Forskilin, for stimulating cAMP
production, or substance for stimulating cGMP production, is
preferred for its ability to increase the rate of percutaneous
absorption of the active agent into and through the stratum corneum
(sc) and viable skin (vs).
[0058] In one particular aspect the present invention provides a
topical formulation for the transdermal delivery of an active agent
having a given polarity and dipole moment; the formulation
includes:
[0059] (A) at least one solvent in which the active agent is
soluble or is modified to solubilize the active agent, and which
has substantially the same dipole moment as that of the combination
of active agent plus solvent system;
[0060] (B) at least one solvent modifier having common structural
features as that of the active agent and comprising an
ethylenically unsaturated polar group containing at least one
functional group containing at least one heteroatom selected from
the group consisting of oxygen, nitrogen and sulfur;
[0061] (C) at least one metabolizable solute modifier comprising a
compound capable of forming a temporary (non-covalently bonded)
complex with the active agent;
[0062] (D) at least one source of cellular activation energy; and,
optionally,
[0063] (E) at lease one skin stabilizer for stimulating the body's
repair mechanisms in response to transdermal migration of the
active agent through the skin.
[0064] The present invention also provides, in a specific
embodiment, a topical formulation for the transdermal delivery of a
medicament (or other active agent) having given polarity, the
formulation including
[0065] (a) at least one non-aqueous non-toxic solvent selected from
the group consisting of lower aliphatic mono- and poly-hydroxy
compounds;
[0066] (b) limonene or lemon oil;
[0067] (c) methylsufonylmethane;
[0068] (d) skin stabilizer comprising at least one compound
selected from the group consisting of aliphatic carboxylic acid
having from about 8 to about 32 carbon atoms, an ester of said
aliphatic carboxylic acid with an aliphatic alcohol having from 1
to about 20 carbon atoms, wherein said ester has a total of from
about 9 to about 36 carbon atoms, Vitamin D.sub.3, and mixtures
thereof;
[0069] (e) solute modifier comprising at least one compound
selected from the group consisting of 3,3'-thiodipropionic acid,
ester thereof, salt thereof, oxindole alkaloid, polyphenolic
flavonoid, sugar adduct of a gluconuride, isoflavones, phosphatidyl
serine, phosphatidyl choline, vitamin D.sub.3 and Vitamin
K.sub.1.
[0070] (f) at least one substance which induces in situ generation
of cAMP or cGMP.
[0071] In accordance with a particularly preferred embodiment of
this aspect of the invention the component (f) is, or comprises,
forskolin or Colforsin, especially forskolin.
[0072] According to still another aspect of the invention there is
provided a method for forming a composition for the topical
application to the skin of a human or other animal for the
transdermal delivery of an active agent of known or predetermined
polarity contained in the composition. The method includes the
steps of
[0073] selecting a solvent in which the active agent is at least
substantially soluble;
[0074] selecting modifying agents for each of the solvent and
active agent such that when the active agent is dissolved in a
solvent system comprising solvent and modifying agent there will
form a complex of at least one modifying agent weakly associated
with the active agent through van der Waals forces and/or hydrogen
bond affinities; said modifying agents comprising at least one
ethylenically unsaturated compound having a polar group and an
oxygen, nitrogen and/or sulfur containing functional group, and at
least one compound for balancing at least one molecular property
characteristic of the solvent system and active agent, said
molecular property characteristic being at least one of
electrostatic energy, non-bonded energy, polarisability and
hydrophobic bonding, and the polarities of the modifying agents are
such that the dipole moment of the active agent closely matches the
dipole moment of the active agent plus solvent system, and
[0075] forming the pharmaceutical composition by mixing each of the
active agent, solvent and modifying agents.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
[0076] The present invention provides a transdermal delivery system
which is able to quickly introduce a medicament or other active
agent through intact skin or mucous membrane or other viable
membrane or external covering of animal, including human, or plant,
while minimizing damage and therefore, minimizing the immune
response of the skin or membrane to this
introduction/challenge.
[0077] While the foregoing and following descriptions are given
with respect to transdermal or percutaneous administration of drugs
or other classes of active agent through human or animal skin, the
principles and compositions disclosed herein are not so limited but
will also be generally applicable to administration of a broad
spectrum of active agents, including medicines, drugs,
pharmacologicals and non-bioactive substances or agricultural
chemicals for treating plants, and other viable animal membranes.
In this regard, it will also be appreciated by those skilled in the
art that certain substances may exert medicinal or pharmacological
activity when used at high concentration while at lower
concentration and/or for a lower extent of transmigration, e.g.,
without substantially reaching beyond the viable skin to the
vascular or capillary network, will exert only a cosmetic effect or
weaker pharmacological activity. It will also be appreciated that
certain compounds, for example, quaternary ammonium compounds, may
in some cases constitute an active ingredient while in other cases
such compounds may be included as modifying agents, skin
stabilizing agent or for other functional effect.
[0078] Accordingly, the term "active ingredient" or "active agent"
or similar term is intended to refer to that ingredient or
ingredients in the formulation which is intended to and expected to
have a half-life of more than a few minutes (e.g., at least about
2, preferably at least about 5 minutes) after introduction into the
body and the only ingredient(s) included to accomplish, in the case
of a drug or other medicinal or pharmacological agent, a
therapeutic outcome, pharmaceutically, or, in the case of an
agricultural agent, an equivalent therapeutic outcome,
agriculturally.
[0079] Furthermore, unless the context indicates otherwise, terms
such as "transdermal" or "skin" should be construed to also include
penetration through the outer layer of various plant forms, such as
trees, flowering plants, cacti, and the like, including, for
example, stems, leaves, shoots and the like.
[0080] Rapid introduction of the active agent enables:
[0081] minimal immune response or anaphylaxis, and
[0082] repetitive dosing over the same area of skin over a short
term or, if needed, for a longer course of therapy.
[0083] In order to accomplish the above and other objectives the
delivery system is designed to (1) create a transient modification
of those aspects of the solvents and solutes which encounter or
trigger the body's defense mechanisms against dermal transmigration
and, (2) minimize or offset any damage done by dermal
transmigration.
[0084] The transient modification (1) is manifested by the
formation of a complex between the solute (active agent) and the
solvent or solvents and modifying agents or modifiers for the
solvent(s) and/or the solute. These complexes are formed as
non-chemical true solutions of the solute in solvent wherein the
components of the complex are held together through weak
association, including van der Waals forces and/or hydrogen bond
affinities but, substantially no covalent bonding. Furthermore, the
carrier for the solute which includes the solvent(s) and modifying
agent(s), as will be described below in further detail, is selected
to have common structural elements (e.g., physical and molecular
orientation, size, shape, etc. and which may be considered as the
"morphological" structure of the compound) which are similar to and
compatible with the structural elements (morphology) of the solute
(active agent) and otherwise exhibits an affinity for the solute
whereby the solute is attracted to and associates with the carrier
to form a 3-dimensional structure which may be analogized to a
Velcro-type mechanism. That is, the carriers of the transdermal
delivery system of this invention are designed for each particular
drug or other medicament or active agent which allows the resulting
complex of active agent to pass through each of the different
layers of the skin's defenses with minimal or no irritation while
carrying the active agent in its intact, non-dissociated state. As
the complex passes through each layer or layers one or more
modifying agents of the complex may be stripped away from the
complex, usually by preferentially bonding or reacting with a
component or components of the skin layer, but without reacting or
disassociating the active agent. This mechanism thus allows the
active agent to reach and be absorbed by or react with its intended
target, usually absorption into the vascular or capillary
network.
[0085] In practice, however, in view of the overall similarities of
common structural elements with and among large classes of
medicaments, it has been possible to design a standard or stock
solution which, with only minor modifications or fine tuning, can
be used for many different active agents.
[0086] The stock solution will generally include (A) solvent(s);
modifying agents including (B) solvent modifier(s); and (C)
metabolizable solute modifier(s); (D) source(s) of cellular
activation energy; and (E) skin stabilizer(s). Other optional
ingredients may also be included, for example, (F) capillary
dilator(s); (G) enzyme activator(s). The active agent is mixed with
the stock solution, further modified, as necessary, to increase
solubility and/or more closely match the molecular properties of
the stock solution plus active agent to that of the active agent,
taking into account one or more effects of the molecular
interactions of molecules in a liquid. Each of these components
will now be described in further detail.
[0087] It is understood that all ingredients used in the
compositions of this invention must, within the applied and
recommended dosages, be non-toxic and safe for human use. Also, all
amounts, parts and percentages in the following description and
appended claims are on a weight basis unless otherwise noted.
(A) Solvents
[0088] The solvent is the principal component of the carrier for
the active agent and, preferably, is one in which the active agent
is soluble or at least substantially soluble or can be made soluble
or become more soluble, by addition of one or more solvent
modifying agents. As used herein, by "substantially soluble" is
meant that the minimum effective dose of the active agent,
generally at least about 0.25 mg, preferably at least about 0.5 mg,
especially preferably about 1 mg, or more, will dissolve in 1 cc of
the solvent(s) or in 1 cc of a mixture of the solvent(s) with
solvent modifying agent(s). Suitable solvents may be selected from
any of the solvents normally used for medicaments, cosmetics,
nutrients or other active agent to be delivered transdermally.
[0089] Preferred solvents include lower alcohols of from about 2 to
about 6 carbon atoms, preferably from 2 to 4 carbon atoms and may
be monoalcohols, such as, for example, ethanol, isopropanol,
sec-butanol, or polyols, such as, for example, ethylene glycol,
propylene glycol, butylene glycol, glycerol. Mixtures of solvents
may be used. Other solvents, such as ketone, e.g., acetone,
methylethyl ketone, ethers, e.g., ethylether, may also be used, in
amounts which will be safe and non-toxic in use.
[0090] While the solvent system is generally non-aqueous water may
be used for water soluble active agents and for those drugs or
other active agents which are stable in the presence of and not
denigrated by the presence of water. Water may also be introduced
as a component of one of the other ingredients, for example, as an
alchohol:water azeotrope, etc. When water is present in the solvent
it will usually constitute less than about 50 percent, preferably
less than about 10 percent, especially, preferably, less than about
2 percent, by weight of the total solvent although more or less may
be used depending on the active agent and so long as the objective
of the invention can be met. Furthermore, as will become apparent
by the examples to follow, the compositions of this invention and
utilizing the principles which will be described in more detail,
hereinafter, may also be formulated as aqueous emulsions, including
wherein the aqueous phase is the major and continuous phase. Such
aqueous emulsions, as is the case with non-aqueous (usually less
than about 5%, especially less than about 2%, of water) solvent
systems, will be rapidly absorbed by the release the active agent
or agents in, typically, less than one minute.
[0091] Generally, the total amount of solvent(s) will be selected
to assure dissolution of the solute and other additives and provide
suitable product viscosity. Generally, the amount of solvent(s)
falling within the range of from about 5 to about 90 percent,
preferably from about 25 to about 75 percent, based on the total
composition, may be used.
(B) Solvent Modifiers
[0092] A solvent modifier is selected to modify the polarity of the
solvent system to closely match that of the active ingredient
(solute). Therefore, solvent modifiers will usually be polar
compounds (from polar ions in solution) and will usually contain a
functional group containing oxygen, sulfur or nitrogen in its
molecule. Also, if the active agent is unsaturated the solvent
modifier will usually also contain double bonds in the
straight-chain or cyclic portion to match the structure of the
active agent. Most importantly, the solvent modifier or mixture of
solvent modifiers enables the solvent system (solvent(s) and
solvent modifier(s)] to form a weak complex with the active agent,
i.e., an association via van der Waals forces and/or hydrogen
bonding, thus yielding a stable composition with a high
solute/solvent ratio. As used herein, "stable" is intended to have
its normal and usual meaning, namely, that the composition may be
stored at room or elevated temperature for one or more days,
usually 30 or more days, without undergoing phase separation. By
"high solute/solvent" ratio is meant at least 0.25 mg solute per
cubic centimeter or solvent (or solvent plus modifying agents) and,
more generally, often amounts of solute exceeding the solubility of
the solute in the solvent alone, or in each solvent of a
multi-solvent system.
[0093] As noted above, solvent modifiers may be individually (or as
a group) selected from substances having structural elements in
common with the active agent. However, it has been found that for
many bio-active compounds and other active agents, a relatively
small group of solvent modifiers facilitate the dissolution of the
active agent and formation of the weak association which enable the
complex of active agent-modifier to pass the defenses of the skin
with minimal irritation without modification of the chemical
structure or stereoscopic configuration of the active agent.
[0094] Thus, particularly favorable results have been obtained by
using as the solvent modifier one or more of lemon oil (or/and
d-limonene), Vitamin E, Pro-Vitamin B, D-Panthenol and
methylsulfonylmethane (MSM).
[0095] The amount of solvent modifier will be selected to result in
the desired solute/solvent ratio, and will depend on various
factors, including, for example, primarily, the polarities, and
polarizabilities, dipole moments, van der Waals forces of each
component, including the solvent, solvent modifier and solute
(active agent).
[0096] In this regard, in order to match the polarities, dipole
moments, of the solute to that of the solvent system the amount of
the individual components of the solvent system will be selected
such that the weighted (molar) average of the dipole moments of the
individual components will be substantially the same as the dipole
moment of the solute in solution.
[0097] Generally, the suitable amount of solvent modifier(s) to
achieve the desired solute/solvent ratio will fall within the range
of from about 0.0001 to about 50%, preferably, from about 0.1 to
about 35%, more preferably, from about 0.1 to about 5%, based on
the total composition.
(C) Solute Modifiers
[0098] The solute modifier may be included in the formulation of
the topical delivery system where necessary to facilitate
dissolution of insoluble or sparingly soluble solutes at higher
concentrations. Solute modifiers which form reversible or temporary
complexes with the solute to facilitate passage through the skin
while minimizing immunological response are especially effective.
The solute modifier will also, optimally, be a nutritional compound
which will metabolized by the body once the solute is released from
the complex.
[0099] Examples of preferred solute modifiers include, for example,
terpenes, such as, for example, Uncaria Tomentosa ("Cat's Claw"),
oxindolealkaloids, quercitrin (glycoside of quercitin), genistein
and its glucoside, genistin, polyphenolic flavinoids, such as found
in concentrated grape seed extracts, scutellarein and other sugar
adduct gluconurides, such as, scutellarin, trans-ferulic acid,
alpha-lipolic acid, sterol, such as, for example, cholesterol and
cholesterol-like compounds and hormones, such as isoflavones,
3,3'-thiodipropionic acid (sulfurated propionic acid), phosphatidyl
serine and choline, Vitamin D.sub.3, Vitamin K.sub.1,
dehydroepiandosterone (DHEA). Still other suitable candidate
compounds include, for example, berberine, piper nigrum (e.g.,
Bioperin.RTM.), phosphatidyl serine, phosphatidyl choline. Another
group of candidate compounds include boswellic acid, hypericum,
phytic acid.
[0100] The selection of the particular complexer will facilitate
movement of the solute-complex past the stratum corneum and viable
skin to its optimal targeted internal circulation system of blood,
lymph or neural; or past the vascular system, to anchor the
bio-active agent, if so desired, deep in the tissues.
[0101] The suitable amount of the solute modifier may be determined
based on such factors as, for example, solubility of the modifier
in the system (e.g. solvent plus solvent modifiers), its molecular
compatibility with the solute, its ability to modify the
polarizability of the solute to increase the concentration
(solubility) of solute in the solvent, etc. Generally, the amount
of solute modifier will be at least about 0.003%, such as, for
example, from about 0.003 to about 5%, preferably from about 0.1 to
about 5%, especially preferably from 0.1 to about 4%, based on the
weight of total composition. Furthermore, it is especially
preferred that the amount of solute modifier or modifiers is
equivalent to the amount of solute to provide a 1:1 interaction
between modifier(s): solute.
[0102] In general, the above described modifying agents, i.e.,
solvent and solute modifiers, as well as other components of the
solvent/carrier delivery system of this invention should preferably
be selected from substances which the body recognizes as usable
building blocks of other physiological systems. This selection
therefore facilitates nearly complete disassociation of the
medicament from the delivery system once in the body. Since these
carrier/complex compounds are reducible to elemental building
blocks of physiology they should do no harm to the body.
(D) Source of Cellular Activation Energy
[0103] The process by which transdermal drug delivery operates
involves moving molecules across chemical and electrical gradients.
Under ordinary tonic conditions, the introduction of materials
through the skin results in chemical cascades that consume
relatively large amounts of energy as the body seeks to defend
itself against the challenge. Therefore, the topical transdermal
delivery system of the present invention, according to one
preferred embodiment, includes a substance which brings stored
energy or the stimulus for release of stored energy on a cellular
level, thereby minimizing energy-negative reactions, which could
lead to sensitization, ACD or anaphylaxis. By including such stored
energy substance, there is a multiplied net increase in available
cellular energy and, accordingly, the potential acceleration of
those reactions which result in the active agent ultimately
reaching its target and being effectively utilized by the body.
[0104] While the composition may be formulated to utilize adenosine
diphosphate (ADP) or nicotinamide adenine dinucleotide (reduced
form) (NADH) or flavin adenine dinucleotide (reduced form)
(FADH.sub.2) such compounds tend to be unstable and, therefore, are
often not preferred.
[0105] There has been identified a group of botanical compounds
which, due, apparently, to so-called signaling mechanisms, induce
high concentrations of enzyme-substrate complexes to be formed,
such as by activation of the N.sub.s (stimulatroy) protein of
adenylate cyclase, thereby resulting in cellular levels of
adenosine 3',5'-cyclic monophosphate (cAMP) approaching the maximal
limits of cellular cAMP concentration.
[0106] In particular, extracts of the plant Coleus Forskholi, and
especially, Forskolin, a labdane diterpenoid, have been found to
have a particular ability to stimulate the production of cAMP in
cells (Refs. 14 and 15). Other extracts of Coleus Forskohli, such
as, Colforsin or coleonol, for example, may also be used.
[0107] Other examples of activation energy sources for stimulating
generation of cAMP, either via precursors or cellular activators,
include, for example, methyl anthines, Saikogenin and Saikosaponin,
Angelacie dahuricae radix (yielding angelic acid), phelopterin,
oxypeucedanin.
[0108] Examples of substances which stimulate cellular production
of cGMP include acetylcholine, cytidene diphosphocholine and
ascorbic acid (Vitamin C).
[0109] The amount of the activation energy source will depend on
such factors as, for example, the mechanism of action of the active
agent, energy of activation (positive or negative) when active
agent encounters its intended receptor (to enhance or decrease cAMP
or cGMP levels), etc. Generally, suitable amounts of forskolin or
acetylcholine or other source of cellular activation energy, will
fall within the range of from about 0.001 to about 0.1%,
preferably, from about 0.001 to about 0.01%, more preferably, from
about 0.001 to about 0.005%, based on total composition. As will be
appreciated by those skilled in the art, cGMP is considered an
antagonist for cAMP. cGMP stimulation will generally be appropriate
for situations where it is desired to enhance immune function, such
as lymphocyte mediated cytotoxicity, during infection,
carcinogenesis, etc. Conversely, cAMP stimulation is generally
appropriate in situations where immune system modulation is
desired.
(E) Skin Stabilizers
[0110] Skin stabilizers may be included in the compositions of this
invention to stabilize the skin prior to passage and to assist the
skin to repair any damage resulting from the transmigration of the
active agent and solvent and other components of the
formulations.
[0111] Suitable skin stabilizers may provide one or more of the
following attributes to facilitate safe and effective dosing of the
active agent while avoiding local or systemic sensitization: form
hydrogen bonds and complex with free radicals: act as a bridge for
collagen, keeping the strand intact temporarily during repair;
stimulate the body's repair mechanisms, modulating prostaglandin,
cytokines and the like; re-stabilze the Elastin complex after the
composition passes through the skin; carry cationic potential,
stimulating nerve transmission, i.e., decreasing nerve
repolarization time at synapses. In addition, preferred skin
stabilizers should be able to be metabolized by the body and should
also shield the medicament or other active agent from the skin's
defense mechanisms by forming suitable complexes which will be
readily uncompleted when the active agent reaches it s intended
site.
[0112] Examples of substances which may function as skin
stabilizers and which may be included in the compositions of this
invention include glycerin monolaurate (e.g., as Lauricidin.RTM.)
and similar fatty acid esters, Vitamin D.sub.3, alkoxy glycerols,
unsaturated fatty acids, such as, eicosapentaenoic acid (EPA),
docosahexaenoic acid (DHA), and gamma-linolenic acid (GLA), Vitamin
E (alpha tocopherol) and the esters, e.g., acetate, and derivatives
thereof, e.g., tocotrienol, D-panthenol, phytantriol,
dehydroepiandosterone (DHEA), pregnenolone, pregnenolone acetate,
esculin, allantoin, ascorbyl palmitate, and the like.
[0113] Suitable amounts of the skin stabilizers may be determine
based on such factors as, for example, type of reaction between
drug (active agent) and skin, between solvent and skin, etc.
Generally, amounts of skin stabilizer, when present, will be at
least about 0.01%, such as, for example, from about 0.05 to about
5%, preferably, from about 0.1 to about 5%, more preferably, from
0.1 to about 2%, by weight, based on total composition. It is
preferred to select stabilizers which will be effective in
stabilizing the skin at as low a concentration as possible.
(F) Other Ingredients
(i). Membrane Permeability Modifiers
[0114] In order to further enhance the ability of the solute to
reach its cellular target the compositions of this invention may
optionally include substances which have the ability to provide a
transitory effect on membrane permeability. Many such substances
are described in the general and patent literature and are often
referred to as skin penetration enhancers, percutaneous absorption
enhancers and similar terms. For instance, the fatty acid esters,
alkoxy glycerols, allantoin, ascorbyl palmitate, and unsaturated
fatty acids mentioned above as skin stabilizers may also sometime
be effective to temporarily enhance cell membrane permeability.
[0115] Other useful membrane permeability enhancers which have a
transitory effect include, for example, Quaternium 28, Quaternium
18, and other cationic quaternary ammonium compound surfactants or
emulsifiers, sulforaphen, cineol terpinen-4-ol, N,N'-diethyl
ethanolamine, N,N'-dimethyl ethanolamine, and the like.
[0116] When used, amounts of the membrane permeability modifiers
may range from about 0.01 to about 5%, preferably, from about 0.01
to about 4%, more preferably, from about 0.05 to about 2%, based on
the weight of total composition.
(ii). Enzyme Activators/Signalling Compounds
[0117] Substances which function as signalling agents, namely, to
provide a signal to the target cell or tissue but without crossing
the cellular boundary either intact or as fragment but which
facilitate the uptake of medicaments or other bio-active agents,
such as by stimulating a particular intercellular response, may
also be included in the subject compositions.
[0118] In particular, mention may be made of substances which
modulate enzyme-substrate (ES) complexes to change the velocity of
reactions and the resulting kinetic energy, such as, for example,
the relative saturation of the enzyme by the substrate. In addition
to the above mentioned functions, Forskolin, sulforaphen and
sulforaphane are believed to function as such enzyme
activators/signalling compounds, by acting as catalysts for the ES
reaction, thereby yielding more rapid orientation of ES completes
to cellular receptors. (see, e.g. Ref. 13, Chapter II, pages
235-253).
[0119] Suitable amounts of such enzyme activators/signaling
compounds will usually be in the range of from about 0.01 to about
0.05%, preferably, from about 0.01 to about 0.02%, by weight, based
on the total composition.
(iii). Capillary Dilators
[0120] Compounds which function as capillary dilators may also be
included in the subject formulations to facilitate passage of the
active agent-complex through the skin and/or provide additional
capillary surface area to facilitate uptake of the active agent
into the vascular system. Compounds which may be incorporated to
function as capillary dilators should be of low toxicity and
readily reversible; suitable compounds include, for example, in
addition to know vasodilators, saponins, Quaternium 28, and
sulforaphen. Preferred compounds should be able to sequentially
open and close ("unzip/zip") the hydrogen bonds in hyaluronic acid
(HA) of elastin as the complexed active agent passes through the
skin.
[0121] Suitable amounts of capillary dilatory, when present, may
range from about 0.1 to about 2%, preferably, from about 0.1 to
about 1.5%, by weight, based on the total composition.
Formulations
[0122] In formulating a carrier system of solvent, modifying
agents, including solvent modifier and solute modifier, and other
components, for the transdermal delivery system of this invention,
several factors may be considered in selecting the particular
ingredients to be included. For example, such factors as (1) the
availability of pure drug versus a salt of the drug; (2) the
solubility of the active agent (usually solubility of a solute in a
solvent may be predicted by the relative dipole moments, the closer
in value the more soluble will be the solute); (3) whether or not
an ingredient will form an adduct or otherwise react with or
degrade the solute or the complex of solute-solvent; (4) common
structural features and physical characteristics of solute and
solvent; (5) hydrophilic/lipophilic balance (for non-polar
solutes); (6) pH (should be matched to that of the active agent,
generally in the range of from about 2.5 to about 8.0, preferably
3.0 to 6.0, especially from about 3 to 4, especially for acidic
active agents and/or to minimize or relieve pain on the exposed
skin where the composition is applied; pH may be increased or
decreased depending on the active agent, e.g., to prevent
ionization or salting effects; the compositions may often be
formulated to be self-buffering but, if necessary, pH may be
adjusted by addition of appropriate acids or bases, or by addition,
for example, of quaternary compounds, ethylene diamine tetraacetic
acid, or the like).
[0123] The topical transdermal delivery system of this invention is
preferably in the form of a lotion or similar free flowing liquid
(e.g., solution, emulsion, etc.). Due to the very rapid absorption
and uptake of the active agent the lotion may be directly applied
to the skin without accommodating for product runoff. For example,
in most cases the formulation is rapidly absorbed in to the skin
within a few to several seconds after application and with a high
e.g.) 90%) percentage of the active agent being transmigrated and
made bio-available.
[0124] However, if desired, various additives, such as thickeners
or gelling agents may be incorporated to form gels or creams
according to standard pharmacological and cosmetic technology.
Alternatively, the topical transdermal composition may also be
incorporated into a TDD system, e.g., patch. However, in all of
these modified forms it is expected that the efficiency of delivery
will be impaired with regard to rate of absorption and amount of
active agent delivered. Therefore, it is generally preferred to
exclude gelling or thickening agents and to apply the formulation
as a liquid (lotion) directly to the skin rather than as a
component of a patch system or directly as a gel.
[0125] A standardized or Stock Delivery System (SDS) for the
solvent/carrier delivery system which as been found to be effective
for a wide range of drugs and other active agents is set forth
below. In the following table the "amount" of each ingredient is on
the basis of an approximately 2 liter system. The amount of the
active ingredient or ingredients which may be incorporated into the
SDS will depend on the nature of the active ingredient, but
generally may range from about 0.1 gram to about 100 grams,
preferably from about 0.1 to about 60 grams per liter of SDS, more
preferably, at least about 0.25 gram, especially at least about 0.5
gram, such as from about 1 to about 45 grams or more, per liter of
SDS, corresponding to a 1 cc unit dosage of from about 0.1 to 100
mg, preferably from about 0.1 to 60 mg, more preferably at least
about 0.25 mg, especially at least about 0.5 mg, most especially at
least about 1 mg, per cubic centimeter (cc). These ranges apply for
both biological (e.g., drug) and non-biologicl (e.g., cosmetic)
active ingredients.
1 Amount Compound Function Broad Intermediate Specific Units
Ethanol, i-propanol, solvent 1000-1200 1050-1150 1125 cc or
sec-butanol Propylene glycol solvent 700-900 750-850 800 cc Natural
Lemon Oil solvent modifier 1-3 1.5-2.5 2.0 g D-Panthenol solvent
modifler 0.5-1.5 0.7-1.2 1.0 g Methyl sulfonyl methane solvent
modifier 1-3 1.5-2.5 2.0 g Glycerol Monolaurate skin desensitizer
2-10 3-8 5.0 g Vitamin D.sub.3 skin stabilizer 0.01-0.5 0.04-0.25
0.1 cc Uncaria Tormentosa solute modifier 1-3 1.2-2.5 2.0 g (15%
polyphenols) (3% oxinodoles) 3,3'-Thiodipropionic solute modifier
0.5-2 0.7-1.6 1.0 g acid Foreskolin (pure) or Source of ATP 0.01-1
0.02-0.6 0.1 g Forskolin (extract 40%) 0.1-2.5 0.1-2.5 1.0 g
[0126] The above Stock Delivery System may be modified, generally,
as a first approximation, as a function of the polarity of the
active agent. Where the solute is soluble in the alcohol/glycol
solvents at the desired level no further solvent modification, as
such, may be required. However, it is often preferable in such case
to modify the system to allow even higher dissolved solute
concentrations so that smaller unit dose or less frequent
applications are feasible.
[0127] In this regard, it is understood that the dipole moment of a
given compound may be taken directly from the literature, when
available, or otherwise measured or calculated by standard
techniques, including commercially available chemical modeling
software packages. Generally, dipole moment is experimentally
determined for an element or compound by suspending a molecule in
an electromagnetic field by measuring the amount of energy (torque)
to rotate the molecule one rotation. Dipole moment is correlated to
van der Waals forces and the number of hydrogen bonds as well as
electrostatic energy of a molecule. Two chemical entities with
approximately the same dipole moment will usually have an affinity
for and be attracted to one another without the necessity for
covalent bonding.
[0128] To determine the dipole moment of the solvent(s) and
modifiers, a weighted average of the dipole moments of the
individual components is used. The weighted average should closely
approximate the dipole moment of the solute. The closer the match
the faster will be the rate of transmigration through the skin.
Generally, the Stock Delivery System will be modified, as
necessary, to move the dipole moment of the solvent solution with
modifying agents and other additives, including the solute, to as
close as possible to that of the solute, preferably within 15%,
especially within 10%, most especially within 5%, of the dipole
moment of the solute.
[0129] More specifically, in accordance withe preferred method for
forming the compositions of this invention, especially for
increasing the amount of drug or other active ingredient which can
be stably carried to solution in the inventive transdermal delivery
compositions, the selection of and the amounts of the ingredients
of the solvent system and other functional additives may be
determined, in the first instance, by balancing the dipole moment
of the active agent relative to the dipole moment of the final
composition. The dipole moment of the final composition is taken to
be the weighted average dipole moments of each individual
ingredient. The weighted average is obtained by calculating the sum
of the mole-moments of each ingredient, where the mole-moment is
obtained by multiplying the amount, in moles, of an ingredient, in
a given volume, e.g., 100 cc, by the dipole moment for that
ingredient. For purpose of this calculation it is assumed that each
ingredient in the compositions acts independently of the other
ingredients. Thus, for example, the dipole moment of any particular
ingredient does not take into account the electronic, e.g.,
repulsive or attractive, effects of other ingredients. However, by
taking concentrations into consideration, that is, by multiplying
individual dipole moments by molar concentrations, a reasonable
approximation of the matching of the system's properties with that
of the solute will generally be achieved.
[0130] As will be described further below, closer and more accurate
matching or fine-tuning of the solute and delivery system may be
achieved by taking other molecular characteristics into
consideration.
[0131] It is also understood that for the above Stock Delivery
system, the stated amounts may be varied, for example, by as much
as about .+-.2.5% or more, depending on the particular active
agent, and the desired degree of matching of dipole moments,
and/or, other molecular properties, particular van der Waals
forces, as discussed above and below. One or more of the compounds
listed above may be omitted or replaced by a functionally
equivalent compound. Some of the ingredients may also provide
functions in addition to those stated in the table.
[0132] For example, glycerol monolaurate, commercially available
under the trade name, Lauricidin.RTM., my be replaced, in whole, or
in part, by other long chain fatty acids or esters.
3,3'-Thiodipropionic acid is primarily effective to promote
delivery of amino acids, glycosides and sugars and, for other types
of active agents, may be omitted, or replaced with other propionic
acid derivatives. Similarly, Uncaria Tormentosa (Cat's Claw) is
primarily effective in delivery systems for primary alkaloid and
terpenoid active agents, and may be replaced with similar
terpenoids, oxindolealkaloids, polyphenolic flavinoids, etc.
Vitamin D.sub.3 also functions to sweep toxins and enhances Na/K
and Mg/Ca pumps.
[0133] In addition to the above ingredients the Stock Delivery
System may also include, for example, phytantriol which has a
similar function to d-panthenol, namely, as a solvent modifier and
for its ability to facilitate refraction from hyaluronic acid (HA)
in skin. When added to the stock formulation its typical amount is
about 1.0 g (per 2 liters).
[0134] Dehydroepiandosterone (DHEA) is another highly useful solute
modifier. When incorporated in or added to the SDS it is usually
effective in amounts of about 100 mg (per 2 liters). Other
optional, but often useful components which may be included in or
added to the above SDS include, oily substances, for example,
conjugated linoleic acid (CLA), medium chain (e.g. C.sub.6-C.sub.8)
mono-, di-, or tri-glycerides, olive oil, Emu Oil, or Melaleuca Oil
(preferably 100% purity) to increase the saturation point of the
system but without facilitating supersaturation;
N,N-diethylethanolamine or N,N-dimethylethanolamine, effective for
modifying dipole moment and aiding in complexing of solute to
modifiers, as well as a skin penetration enhancer; pregnenolone or
pregnenolone acetate, as a drug complexer and/or for increasing
transdermal migration and/or skin stabilization; transferulic acid
and alpha lipolic acid, as anti-oxidants and for controlling the
re-complexing of the HA in elastin and skin, also functioning as a
solute complexer; Berberine, as a signaling mechanism for enhancing
more efficient uptake of certain medicaments by cells.
[0135] It is understood that the above are only exemplary of
suitable additives and modifications to the transdermal delivery
systems of the invention and that other additions, deletions or
modification can be made within the guidelines provided herein and
by the more detailed examples of follow.
[0136] While the Stock Delivery System as above or appropriately
modified for the particular active agent of interest will usually
be formulated in large size batches the compositions of this
invention including the active agent will often preferably be
provided for dispensing in unit dosage forms, as well known in the
art. For example, individual sealed packages or metered dosage pump
type containers for dosing about 1 cc of composition, may be
provided to contain sufficient active agent for a single
application.
[0137] Laminar matrix transdermal systems are designed to leech
medicament through the stratum corneum into the dermis and the
vicinity of the cutaneous plexis of the capillaries. This is a slow
process, usually requiring hours to days to deliver the maximum
available dose. Since deep penetration is generally not possible
for these systems without external iontophoretic accelerators, they
are limited to delivery of medicaments which are systemically
efficacious in relatively small doses, and generally only deliver
one third of the drugs with which they are loaded.
[0138] In contrast, the transdermal delivery system of this
invention can effectively delivery at least about 90% or more of
the medicament rapidly through the skin to the underlying fatty
tissue. This delivery may be accomplished in only a few to several
tens of seconds or just a few minutes or less. In some cases, it
may be desirable to slow down the rate of trans-migration, for
example, to direct the dose of the medicament for systemic
administration via the capillary net of the dermis. Particular
medicaments or which systemic administration is often indicated
include, for example, hormones, vitamins, systemic antibiotics.
[0139] Such slowing down may be accomplished by modifying the stock
delivery system so that there is mismatching of the dipole moments
of the solute and the solvent(s) and modifying agent(s), for
example, at least about 15% or more difference, such as about 15 to
about 35% variation, especially from about 20 to 30% variation. By
so varying the dipole moments and/or other molecular
characteristics, of the solute and the SDS for the solute a more
shallow penetration of the solute and/or a less acute uptake curve
may be achieved. Here too, however, the resulting complex of the
solute with the SDS components will effectively shield the
medicament (active agent, solute) from the body's defenses, yet
will not "slip" through quite as effectively or efficiently. This
dipole moment mismatching, may therefore, be effectively utilized
to insure that, at any given time, more medicament is in the
general vicinity of the cutaneous plexis and available to be picked
up by the capillary network for systemic delivery.
[0140] In the case of therapy requiring slower delivery, the system
may be balanced to take longer to get to the strata of the target,
by emphasizing lipophilic binding affinities in the solute
modifiers. Some medicaments may safely be moved past the cutaneous
plexis and stored in the fascia beneath the capillary net. This
level is not as well defined by cell-mediated immune response and
may serve as a natural storage and release matrix for delivery of
these medicaments.
[0141] Slower transmigration and/or bioavailability may also often
be achieved, for example, by modifying the hydrophilic-lipophilic
balance (HLB) of solute modifiers and/or by "shielding" the
medicament with lipids which will increase the time to
de-complexing of the solute-modifying agent complex.
[0142] While the above discussion focuses on the matching of the
dipole moment of the active agent with the SDS, e.g., solvent(s),
solvent modifier(s) and solute modifier(s), and will allow one
skilled in the art to effectively formulate topical delivery
systems according to the invention, still further refinements, and
improved consistency, may be obtained by further taking into
consideration other parameters which are characteristic of the
physicochemical properties of the solute (active ingredient, e.g.,
drug) and the carrier components of the topical delivery system. In
particular, the following properties of the solute and the delivery
or carrier system can be measured or calculated or may, in some
cases be obtained directly from the published literature: entropy,
enthalpy, Free energy, Potential energy, Kinetic Energy. Dipole
Moment, Surface Interaction parameters. Matching these various
parameters between the solute and the delivery system will
facilitate the transdermal delivery of the solute to the intended
target.
[0143] More particularly, the following is a more specific overview
of how the solvents, modifying agents and other enhancing agents
and additives may be compounded together to standard stock delivery
carrier system and how any particular medicament molecule (or other
active agent) is evaluated and the delivery system consequently
modified to maximize solubility and optimize transmigration to the
target level of skin or tissue.
[0144] Many molecular properties come into play with molecules in
close proximity. A representative list of these includes stearic
energy, heat of formation, dipole moment, charge density,
non-bonded energy, COSMO solvation in water, electrostatic
potential, electron spin density, hyperfine coupling constants,
atomic charges, polarisability and others such as IR vibrational
frequencies. According to the present invention, the molecular
evaluation system is particularly concerned with 4 of the several
forces in play on the molecules of the system and the medicament.
These four elements are:
[0145] Electrostatic Energy
[0146] Non-bonded Energy
[0147] Polarisability
[0148] Hydrophobic Bonding
[0149] These four elements constitute a graded, increasingly fine
approximation to balance of those factors and vectors which are
predictive of dissolving a particular medicament in a liquid
medium, the aggregation of which is designed to rapidly
transmigrate the lipid domains of the SC by means of temporary
disruption, continue traverse through the VS to the capillary
plexis beneath or past the plexi into the fascia lata or deeper as
required, the entire process being accomplished so as to assist in
repair of damage secondary to domain modulation and minimization of
hapten formation and any subsequent cascade.
[0150] Electrostatic Energy
[0151] The Electrostatic energy which is the first parameter of
intermolecular forces which may be controlled can be described with
the equation: 1 E Electrostatic = i j q i q j D r i j
[0152] where the Electrostatic energy is a function of the charge
on non-bonded atoms, q; their inter-atomic distances, r.sub.ij and
a molecular dielectric expression, D, which accounts for the
attenuation of electrostatic interaction by the environment, e.g.
between the solvent and solute modifiers and between the system and
the medicament itself.
[0153] In a preferred embodiment, the electrostatic energy may be
modeled by the Chem 3D software, available from Cambridge Soft
Corporation, Cambridge, Mass., using atomic charges for charged
molecules and bond dipoles for neutral molecules. There are three
interactions which are accounted for through the Chem 3D software.
These include Charge/Charge interactions; Dipole/Dipole
interactions; and Dipole/Charge interactions. These interactions
are calculated for each molecule of the carrier system and the
medicament separately and then a weighted molar average calculation
accounts for the system as a whole, and this quotient is balanced
against the medicament as to gross order of magnitude. Each type of
interaction uses a different form as shown below:
[0154] Charge/charge contribution: 2 E = 332 i j q i q j D r i
j
[0155] where the value 332 converts the results to units of
kcal/mole.
[0156] Dipole/dipole contribution: 3 E = 14.4 i j i j D r i j ( cos
- 3 cos i cos j )
[0157] where the value 14.4 converts the result from ergs/mole to
kcal/mole, is the angle between the two dipoles, .mu..sub.i and
.mu..sub.j, .alpha..sub.i and .alpha..sub.j are the angles which
the dipoles form with the vector r.sub.ij, connecting the two at
their midpoints, and D.mu. is the effective dielectric
constant.
[0158] Dipole/charge contribution: 4 E = 69.1 i j q i j r 2 i j D D
q ( cos j )
[0159] where the value 69.1 converts the result to units of
kcal/mole.
[0160] Bond dipole parameters, ,.sub..mu., for each atom pair are
stored in bond stretching parameter table of the Chem 3D software
or may be obtained from the literature or other available
databases, such as, for example, Cambridge Structure Database, or
experimentally. The charge q is stored in the Molecular Mechanics
(MM2) atom types table. The molecular dielectric is set to a
constant value between 1.0 and 5.0 in the MM2 Atom types table.
[0161] Non-Bonded Energy
[0162] The second parameter which may be manipulated and balanced
is Non-bonded Energy. Molecular mechanics describes the energy of a
molecule in terms of a classically derived potential energy
functions and the parameters used for their evaluation are known as
"force field" parameters; Molecular mechanical methods are based on
the following principles:
[0163] Nuclei and electrons are lumped together and treated as
unified atom-like particles.
[0164] Atom-like particles are regarded as spheres.
[0165] Bonds between particles are viewed as harmonic oscillators
and therefore subject to principles of harmonic conservation of
energy.
[0166] Non-bonded interactions between these particles are treated
using potential functions derived from classical mechanics.
[0167] Individual potential functions are used to described the
different interactions; including bond stretching, angle bending,
torsional or bond-twisting energies and non-bonded or through-space
interactions (the interactions of most concern in the subject
liquid system).
[0168] Potential energy functions rely on empirically derived
parameters, e.g., force constants, equilibrium values, that
describe the interactions between sets of atoms.
[0169] The sum of interactions determine the spatial distribution
or conformation of atom-like particles.
[0170] Molecular mechanical energies have no meaning as absolute
quantities. They can only be used to compare relative stearic
energies between two or more conformations of the same
molecule.
[0171] Molecular theory typically treats atoms as spheres and bonds
as springs. The mathematics of spring deformation (Hooke's Law) is
used to describe the ability of bonds to stretch, bend and twist.
Non-bonded atoms defined as greater than two atoms apart, interact
through van der Waals attraction, stearic repulsion, and
electrostatic attraction/repulsion described above. These
properties are easiest to describe mathematically when atoms are
assumed to be spheres of characteristic equal radii.
[0172] The total potential energy, E.sub.TP, of a molecule can be
described by the following summation:
E.sub.TP=E.sub.S+E.sub.B+E.sub.T+E.sub.NBI
[0173] where E.sub.S is Stretching Energy, E.sub.S is Bending
Energy, E.sub.NBI is Torsion Energy and E, is Non-bonded
Interaction Energy. The first three terms are the so-called bonded
interactions. In general, these bonding interactions can be viewed
as a strain energy imposed by a model moving from some ideal
zero-strain conformation. The last terms, which represents
non-bonded interactions, is the variable which is of most concern
for the present liquid compositions.
[0174] The non-bonded energy represents the pairwise sum of the
energies of all possible interacting, non-bonded atoms i and j with
a pre-determined "cut-off" distance. The non-bonded energy accounts
for repulsive forces experienced between atoms at close
proximities, defined as less than 2 .ANG. and for the attractive
forces felt at longer distances, defined as greater than 2 uniform
molecular radii. It also accounts for their rapid fall-off as the
interacting atoms move farther apart by a few Angstroms.
[0175] Repulsive forces dominate when the distance between
interacting atoms becomes less than the sum of their contract
radii. This repulsion can be modeled by the following equation
which combines an exponential repulsion with an attractive
dispersion interaction (1/R.sup.6):
E.sub.van der
Waals=.SIGMA..sub.i.SIGMA..sub.j.epsilon.(290,000e.sup.-12/5-
R-2.25R.sup.-6)
[0176] where 5 R = r i j R i * + R j *
[0177] where R.sub.i.sup.* and R.sub.j.sup.* are the van der Waals
(VDW) radii of the atoms, epsilon (.epsilon.) is the depth of
attractive potential energy and consequent relative ease with atoms
can be pushed together and r.sub.ij is the actual distance between
the atoms.
[0178] At short distance, the above equation favors repulsive over
dispersive interactions. To compensate for this at short distance
this term is replaced with:
E.sub.van der Waals=336.2
.SIGMA..sub.i.SIGMA..sub.j.epsilon.R.sup.-2
[0179] For certain interactions, values in the VDW interactions
parameter table of the ChemPro 3D software package are used instead
of those in the MM2 atom types table. These situations include
interactions where one of the atoms is very electronegative
relative to the other, such as in the case of water.
[0180] Polarisability
[0181] The third parameter allowing for modulation towards the
balance of medicament and carrier system is polarization.
Polarisability values are calculated by Chem3D software using the
following equations. Of special concern is the orientation
polarization (P.sub.d) caused by the preferential alignment of
permanent dipoles in the direction of the electrical, or in this
case, the bio-electrical field. To compute P.sub.d, the magnitude
of the dipole moment M induced in a molecule by the field acting on
it must be factored in. It is assumed that this induced moment is
proportional to the strength of the field F, so that:
m=.alpha.F
[0182] The proportionality factor a is called "polarisability." It
is the induced moment per unit of field strength. Note that a has
the dimensions of volume since: 6 Q r ( Q / r 2 ) = r 3
[0183] The polarisability of a hydrogen atom is 4.5a.sup.3, which
is close to the volume of a sphere of radius equal to that of the
Bohr orbit, 4/3.pi.a.sub.0.sup.3=4.19a.sub.0.sup.3. The
polarisability of an atom is a good measure of its volume.
[0184] If the dielectric is not a gas, as is the case with the
present liquid compositions, the influence of the surrounding
molecules has to be accounted for in order to estimate the field
that acts to polarize a given molecule or atom-like particle. For
gases at high temperatures, for non-polar liquids, and for dilute
solutions of polar solutes in non-polar solvents, the effective
field F is often taken to be: 7 F = E + 4 3 P
[0185] It follows then that 8 m = E + 4 3 P
[0186] from which is obtained 9 P m = - 1 M + 2 p = 4 L 3
[0187] where 10 P = 3 ( F - E ) 4
[0188] is the polarization of individual molecules, E is electrical
energy and P.sub.m is called the molar polarization.
[0189] Polarization is a calculation in the X, Y, and Z planes and
then averaged for each molecular constituent of the carrier and
then for the carrier versus the medicament. Bond stretch parameters
are not considered. The carrier and medicament are viewed as
Atom-like particles. For the same reason energies of vibration and
libration defined above, may be ignored.
[0190] Hydrophobic Bonding
[0191] The fourth and finest refinement of the balance is
accomplished by modulating Hydrophobic Bonding. These parameters
are calculated from the average potential of each Hydrogen atom on
each specific constituent molecule. This last factor becomes
particularly important in hydrophobic lipophilic systems and
obviously critical in protein delivery, since methylated fatty
acids replace alcohol or propylene glycol as the primary solvent
for the system. This averaged value can be seen as the capacity of
the carrier for low polarity, lipid solubility and compares the
potential of the Hydrogen molecules on the outer surface of the
solvent and solute. Hydrophobic Bonding values may be calculated by
Chem3D software.
[0192] In practice, a data base on the primary, secondary, and
tertiary ingredients of a standard delivery system as well as
alternate solvents and modifiers for medicaments requiring a
different approach such as proteins or very large polymerized
molecules will be established. By "primary," "secondary" and
"tertiary" is meant ingredients which exert major or gross changes
in system properties, e.g. dipole moments, van der Waals forces,
etc. (Primary); ingredients which make only small changes in system
properties (secondary) and ingredients which can be used for
"fine-tuning" the system properties to match the properties of the
solute (tertiary).
[0193] The following tables are typical data sheets generated by
the Chem3D software. These charts confirm the independent
experimental solubility data and also, in Tables 1-3, show how
modulation of the carrier system allows a higher dose of the test
medicament, Diosgenin (MW=414.61). Table 1 shows balance (and
maximum solubility) at 0.25 grams in a typical Stock Delivery
System (SDS) according to the invention; Table 2 shows that
modulating the system by adding isopropyl alcohol increased the
solubilized dose to 1.2 grams, a nearly 5-fold increase. Table 3
shows that when the van der Waals forces of the delivery system
with and without drug are mismatched, the system becomes unstable,
namely, the solubility limit of the drug is exceeded and a
precipitate forms when the composition is allowed to stand
overnight.
[0194] It is pointed out, however, that the formulations shown in
the following Tables, and which are based on the above described
Stock Delivery System, were originally prepared without benefit of
the use of the Chem 3D software and included omission of several
different modifiers. Modifications to the SDS to effect
solubilization and increase solute solvent ratios were made by the
inventor on the basis of knowledge of how and where the solute
(drug) works in the body and using this information to make
intuitive predictions of how the solute would interact with the
surrounding molecules of the SDS, such as induced polarities
relative to other molecules; induction of electric fields due to
influence of surrounding molecules; hydrophobic versus hydrophilic
properties, etc., while always taking into consideration the
desired functional effects contributed by each ingredient. Thus, it
should be understood that these tables provide a more rationalized
basis and unifying theory of the operation of the invention and
should allow for preparing stable compositions containing different
solutes at high solute/solvent system ratios. For example, using
computer modeling of chemical structure can often facilitate
understanding of polarizabilities and possible interactions between
the drug and other potential components of the system. Again, any
potential component must be compatible with the active agent,
namely, not form or induce a chemical reaction or covalent
bonding.
[0195] For any medicament to be delivered, similar numbers may be
generated whereby the carrier system will be balanced against the
medicament.
[0196] It will be appreciated that the modifications and
calculations in the tables follow the same general principles as
described previously for balancing dipole moments using the sum
mole-moments. In this case , it is the sum of the mole-van der
Waals forces which is calculated and which appears to provide an
effective correlation and predictor of success in formulating
stable compositions with high solute/solvent ratios.
[0197] It should also be appreciated that the use of computer
software, for chemical structure modeling, such as Chem3D software,
while speeding up the ability to fine tune the transdermal delivery
system, is not essential since solubility and other data can
generally be obtained from the literature or by direct
experimentation, using the general guidelines and concepts
discussed previously.
[0198] As in the case for balancing of dipole moments, in the
present invention, the formulation of the solvent carrier system,
which may be the above described SDS or any other appropriate
non-aqueous or aqueous solvent-carrier system for the particular
active agent or active agents and the particular disease or other
condition to be treated, may be balanced for mole-van der Waals
forces, when the active agent or agents are added thereto, as a
predictor of solubility of the desired amount(s) of active agent(s)
by bringing the sum of the mole-van der Waals forces for the
solvent carrier system with active agent(s) to within .+-.20%,
preferably within .+-.15%, especially preferably within .+-.10%,
and most especially preferably within .+-.5%, of the sum of the
mole-van der Waals forces of the solvent carrier system without the
active agent(s).
[0199] When the difference between the sum of the mole-van der
Waals forces of the solvent carrier system plus active agent is
greater than about 20%, especially greater than about 15%, of the
sum of mole-van der Waals forces for the solvent carrier system
without active agent the desired amount of active agent will tend
to be insoluble in the solvent carrier system or may precipitate
from solution upon standing overnight. In the case of compositions
containing two or more active agents, if the mole-van der Waals
forces are not closely balance, as described above, one or more of
the active agents will tend to be insoluble in the solvent carrier
system or otherwise precipitate out of solution.
2TABLE 1 Diosgenin Base Solution Moles Compound Mole Wt. Amt.
(grams) Amt./100 cc Moles VW Forces VW Forces Diosgenin 414.6
0.25.sup.1 0.0006 26.88 0.016 Ethanol 46.07 1068.75 54.38 1.18 2.01
2.375 Water 18 56.25 2.86 0.16 0 0 Propylene Glycol 76.01 828 42.13
0.55 4.10 2.272 limonene 136.24 2 0.10 0.0007 6.22 0.0046 Vitamin E
430.17 1 0.50 0.00012 20.60 0.0024 D-Panthenol 205.25 1.05 0.05
0.00026 10.82 0.0028 Methylsulfonyl- 94.13 2 0.10 0.0011 -0.34
-0.0004 methane (MSM) Lauriciden 181.97 5 0.25 0.0014 14.04 0.020
Oxindole 295 0.06 0.003 1.0E-05 13.66 0.0001 Thiopropionic 178.21 1
0.05 0.0003 6.61 0.001 acid Forskolin 410 0.2 0.01 2.5E-05 25.05
0.0006 Totals 1965.31 100 stock solution + 4.694 diosgenin = stock
solution w/out 4.678 diosgenin = difference = 0.016 percent
difference = 0.34% .sup.1Solubility limit determined
experimentally
[0200]
3TABLE 2 Diosgenin System One Mole VW Amt/ Forces Compound Mole Wt.
100 cc Moles VW Forces One Diosgenin 414.6 1.2.sup.1 0.003 26.88
0.078 Ethanol 46.07 77.73 1.69 2.01 3.395 Isopropyl 60.1 8.18 0.14
1.94 0.264 Alcohol Water 18 2.30 0.13 0 0 Propylene 76.01 10.04
0.13 4.10 0.541 Glycol limonene 136.24 0 0 0 Vitamin E 430.17 0 0 0
D-Panthenol 205.25 0 0 0 MSM 94.13 0 0 0 Lauriciden 181.97 0.3 0.00
14.04 0.023 Oxindole 295 0.06 0.0002 13.66 0.003 Thiopropionic
178.21 0 0 6.61 0 acid Forskolin 410 0.2 0.0005 25.05 0.012 Totals
100 Diosgenin SysOne 4.316 Mole VWF STOCK SOL. 4.238 Diosgenin
SysOne 0.07 minus Stock Sol. Percent Difference 1.84 .sup.1Stable
solution; effective for transdermal delivery
[0201]
4TABLE 3 Diosgenin System Two Amt/ Mole VW Compound Mole Wt. 100 cc
Moles VW Forces Forces Diosgenin 414.6 1.5.sup.1 0.0036 26.88 0.097
Ethanol 46.07 77.49 1.682 2.01 3.385 Isopropyl 60.1 8.16 0.136 1.94
0.264 Alcohol Water 18 2.29 0.127 0 0 Propylene 76.01 10.00 0.132
4.10 0.539 Glycol limonene 136.24 0 0 0 Vitamin E 430.17 0 0 0
D-Panthenol 205.25 0 0 0 MSM 94.13 0 0 0 Lauriciden 181.97 0.3
0.0016 14.05 0.023 Oxindole 295 0.06 0.0002 13.66 0.003
Thiopropionic 178.21 0 0 6.61 0 acid Forskolin 410 0.2 0.0005 25.05
0.012 Totals 100 Diosgenin Sol 4.323 Mole VWF Two STOCK SOL. 4.226
Diosgenin Sys Two 0.097 minus Stock Sol. Percent Difference 2.30
.sup.1Solution not stable; precipate forms upon standing
overnight.
[0202] The following Table 4 illustrates how the balancing of molar
van der Waals forces can be utilized as a predictor of the
solubilization of amitriptyline in the stock delivery system. In
this case the calculations for balancing molar van der Waals forces
were made first using the Chem3D software and the solutions were
thereafter formulated in the laboratory. The amount predicted to
dissolve, 2.08 gm per 100 c.c., was within experimental error of
the actual amount which would dissolve in the laboratory
experiment. In this case, the system was balanced by increasing the
amounts of methylsulfonylmethane and ethanol and decreasing the
amount of propylene glycol.
5TABLE 4 SDS SDS Mod.SDS SDS + Drug SDS + Drug Mole Wt Amt/100
Moles Amt/100 Moles VW Forces VDW-Molar VDW-Molar Amitriptyline
277.41 2.00 0.007 2.08 0.0075 15.99 0.115 0.120 MSM 94.13 0.20
0.0021 -0.39 -0.0008 Ethanol 46.07 54.38 1.18 61.99 1.35 2.01 2.375
2.708 Water 18 2.86 0.16 1.86 0.16 0 0 0 Propylene glycol 76.01
42.13 0.55 33.70 0.44 4.10 2.272 1.817 limonene 136.24 0.10 0.0007
0.10 0.0006 6.22 0.005 0.004 Vitamin E 430.17 0.05 0.0001 0.05
9E-05 20.60 0.002 0.002 D-panthenol 205.25 0.05 0.0003 0.05 0.0002
10.81 0.003 0.002 MSM 94.13 0.10 0.001 0.10 0.0009 -0.39 -0.0004
-0.0003 Lauriciden 181.97 0.25 0.001 0.25 0.001 14.05 0.020 0.016
Oxindole 295 0.003 1E-05 0.003 8E-06 13.66 0.0001 0.0001
Thioproprionic acid 178.21 0.05 0.0003 0.05 0.0002 6.60 0.002 0.002
Forskolin 410 0.01 2.5E-05 0.01 2E-05 25.05 0.0006 0.0005 100 SDS +
Drug = 4.794 4.670 SDS = 4.679
[0203] The following Table 5 illustrates the calculation of the
mole-moment for a typical Stock Delivery System (SDS) according to
the invention:
6TABLE 5 SDS Dipole Mole Compound Mole Wt Amt Used Amt/100 Moles
Moment Moment Ethanol 46.07 1068.75 54.38 1.18 1.78 2.10 Water 18
56.25 2.86 0.16 1.85 0.29 Propylene Glycol 76.01 828 42.13 0.55
1.45 0.80 limonene 136.24 2 0.10 0.0007 0.365 0.0003 Vitamin E
430.17 1 0.05 0.0001 0.835 9.9E-05 D-panthenol 205.25 1.05 0.05
0.00026 4.33 0.001 MSM 94.13 2 0.10 0.0011 4.51 0.005 Lauriciden
184.97 5 0.25 0.0014 3.08 0.004 Oxindole 295 0.06 0.003 1.03E-05
1.42 1.5E-05 Thiopropionic Acid 178.21 1 0.05 0.00029 3.94 0.001
Forskokin 410 0.2 0.01 2.5E-05 4.48 0.0001 1965.31 100 SUM Mole
3.20 Moments
[0204] Table 6 shows van der Waals force values for various
hormonal active agents:
7 TABLE 6 Hormone VW Forces Testosterone 16.17 Estrone 13.74
Estradiol 14.87 Estriol 13.89 DHEA 16.48 17 OH Pregnonolone 18.16
Pregnenolone 16.78 Progesterone 15.93 Diosgenin 26.88
[0205] Use of the invention methodology for forming a topical
composition for transdermal delivery of hydroxyzine at a
predetermined or target dosage of about 45 to 50 mg per cubic
centimeter is illustrated in the following Table 7:
8TABLE 7 SDS.sup.1 H-1.sup.2 H-2.sup.3 H-O H-1 H-2 Mole Amt/ Amt/
Amt/ Sol Two dipole Mole VW Mole- Mole- Mole- Compound Wt 100 100
100 Moles Moles Moment Moment Forces VDW VDW VDW Hydroxyzine 374.91
5.0 5.0 4.55 0.013 0.012 0.57 0.0076 22.72 0.303 0.303 0.276 MSM
94.13 2.0 1.0 0.021 4.51 0.096 -0.39 -0.0080 -0.0083 Ethanol 46.07
54.38 54.38 58.07 1.18 1.26 1.78 2.10 2.01 2.375 2.375 2.536 Water
18 2.86 2.86 0.16 1.85 0.29 0 0 0 0 Propylene 76.01 42.13 42.13
38.30 0.55 0.50 1.45 0.804 4.10 2.272 2.272 2.065 Glycol limonene
136.24 0.10 0.001 0.10 0.0007 0.36 0.0002 6.23 0.0046 0.0046 0.0042
Vit E 430.17 0.05 0.051 0.0001 0.83 0.0001 20.00 0.0024 0.0024
0.0022 D-panthenol 205.25 0.05 0.053 0.003 4.33 0.001 10.82 0.0028
0.0028 0.0026 MSM 94.13 0.10 0.10 0.001 4.51 0.005 -0.39 -0.0004
-0.0004 -0.0004 Lauriciden 181.97 0.25 0.25 0.001 3.08 0.004 14.05
0.0196 0.0196 0.017 Oxindole 295 0.003 0.003 1E-05 1.42 1.5E-05
13.66 0.00014 0.00014 0.0001 Thiopropionic 178.21 0.05 0.05 0.0002
3.94 0.001 6.61 .0019 0.0019 0.0017 acid Forskolin 410 0.20 0.20
0.005 4.48 0.002 25.05 0.0006 0.0006 0.0006 4.982 4.973 4.898
.sup.1Initial Attempt added Hydroxyzine to Stock Sol. .sup.2First
modification added additional MSM .sup.3Second modification
increased Ethanol and reduced additional MSM
[0206] Although not wishing to be bound by any particular theory of
operation, it is believed that the most adequate theory describing
how the medicament finds its way, once inside the body, to the
intended target site, is the so-called "information theory." This
theory asserts that medicaments are biologically active compounds
for which the body develops particular affinities when challenge is
present due to degenerative disease, infection or trauma. The
affected tissues selectively attract and bind these substances as
they encounter them in humor or tissue mediums while normal tissues
seek to deflect the compounds away. Once the carrier
medicament-complex arrives in the vicinity of the diseased or
"abnormal" tissue, the attraction of the tissue receptors overcomes
the weak association between the carrier and the medicament and the
medicament is released intact and taken by the needy tissue. By a
similar mechanism modifying agent components may be stripped from
the complex prior to arriving at the needy tissue.
[0207] Examples of medicaments which may be incorporated in the
transdermal delivery system of this invention are not particularly
limited. Generally, any medications previously used or suggested as
useful for delivery by any means, including transdermally, whether
by patch or ointment or other topical formulation, may be used in
this invention. Some areas where it is envisioned that the subject
TDS will have particular benefits include pain relief (for safer
dose of a prescription or non-prescription analgesic locally to the
site of pain); antibiotic delivery, e.g., Ciprofloxacin (permitting
higher dosages at the locus of the infection to above safe systemic
levels); corticosteroids (for treating inflammatory indications
with delivery bypassing the liver and minimizing systemic side
effects); hormone replacement therapy (e.g., to deliver
tri-estrogens to the non-carcinogenic androgen pathway along with
the inclusion of mechanisms to offset the negative cosmetic side
effects of this pathway); isoflavinoid cancer therapies (allowing
high concentrations); hypertoxic chemotherapies (to raise local
concentratiosn with reduced impact systematically).
[0208] More generally, any of the drugs listed in, for example, The
Merck Index, or other pharmacopeia, may be used. For example,
mention may be made of hormones, such as, DHEA sulphate, 17-hydroxy
pregnonolone, testosterone, tri-estrogen; topical anesthetics, such
as, lidocaine, procaine, dimethocaine, salicylic alcoholic;
analgesics, such as, for example, morphine, Demerol.RTM.,
Fentanyl.RTM., sufentanil, acetaminophen, acetylsalicylic acid,
bucetin, difenamizole, enfanamic acid, etodolac, fenoprofen,
Ibruprofen, naproxen, suprofen; steroids, such as, for example,
pregnonolone, pregnonolone acetate, progesterone; ACE-inhibitors;
.alpha.-adrenergic agonists; .beta.-adrenergic agonists;
.alpha.-adrenergic blockers; .beta.-adrenergic blockers;
adrenocortical steroids; adrenocorticotropic hormones; alcohol
deterrents; anabolic steroids; androgens, such as testosterones;
anorexics; antacids; anthelmidines; antiacne and keratolytics;
antiallergic, decongestants, antihistamines, glucocorticoids;
antialopecia agents; antiandrogens; antianginals; antiarrhythimics;
antiarthritic/antirheumatic; antiasthmatic; antibacterial
(antibiotics), e.g., Ciprofloxacine, antifungal and antiviral
agents; antinenoplastics; anticholinergics; anticoagulants;
anticonvulsants; antidepressants, e.g., 5-hydroxytriptophan;
antidiabetics; antidiarrheal agents; antidiuretics; antidotes
(e.g., acetaminophen poisoning, cyanide poisoning, heavy metal
poisoning); antisyskinetics; anti-eczematic agents; antiemetics;
antiestrogens; antihistamines; antihyperlipoproteinemics;
antihyperphosphatemics; antihypertensives, such as, e.g.,
clonidine, or other "beta-blockers"; antihyperthyroids;
antihypotensives; antithypothyroids; anti-inflammatory (steroidal
and non-steroidal, including, for example, the above-exemplified
analgesics and other NSAIDs and steroidal inflammatories);
antimalarial; antimigraines; antineoplastic agents;
antiparkinsonian agents; antipruritics; antipsoriatics;
antipsychotics; antipyretics; antiseptics and disinfectants,
antispasmodics; antithrombotics; antitussives; antiulceratives;
anxiolytics; astringents; benzodiazepine agonists; bronchodilators;
calcium channel blockers; cardiotonics; chelating agents;
choleretics; cholinergic; central nervous system (CNS) stimulants;
digestive aids; diuretics; enzymes; estrogens; glucocorticoids;
gonad-stimulating principles; gonadotropic hormones, other
hormonal-type substances, such as, for example, melatonin,
serotonin, liothyronine, histamine H.sub.2-receptor antagonists;
immunomodulators; immunosuppressants; lactation stimulating
hormones; LH-RH agonists; liptropics; monoamine oxidase inhibitors;
muscle relaxants; narcotic antagonists; oxytocin agents;
progestogen; prolactin inhibitors; prostaglandin/prostaglandin
analogs; protease inhibitors; sedatives and hypnotic agents;
vasodilators (cerebral, coronary and peripheral); vasoprotetants;
vitamins.
[0209] In particular, the present invention may offer its most
notable benefits in connection with active agents of high molecular
weights for which prior known topical transdermal delivery systems
were not effective or applicable. Thus, the compositions of this
invention are highly useful and effective for active agents having
molecular weights in excess of about 325 Daltons, especially higher
than about 350 D, more especially higher than about 375 D and most
especially higher than about 400 D, for example, 500 D and higher.
Extremely high molecular weight substances such as calcitonin
(MW=4500); human growth hormone (MW=22,000) and other hormones,
polypeptides and protein, may be solubilized in accordance with
this invention by appropriate selection of solvents, e.g., fatty
acid, and utilizing appropriate phospholipid chemistry for the oil
phase and hydrophilic/lipophilic modulation by appropriate
modifying agents. Moreover, the compositions of this invention may
be formulated to delivery, per unit dosage, usually about 1 cc, at
least about 0.25 mg, especially at least about 0.5 mg, especially,
up to about 1 mg or higher of active ingredient, including such
high molecular weight substances as described above.
[0210] Moreover, the effective dosage of the medicaments are
generally substantially less than the effective dosage when
administered orally or intravenously or intramuscularly; and a rule
of thumb is that topical transdermal dosages are approximately
one-seventh of the oral dosage. However, higher or lower dosages
may be required or advantageous depending on the symptoms, whether
intended for local or systemic administration, etc.
[0211] The invention will not be described with reference to the
following non-limiting illustrative examples.
[0212] In the following examples the above described SDS was used,
in the amounts indicated. Unless otherwise noted all of the
ingredients are USP grade.
EXAMPLE 1
[0213] The following composition (lotion) using the above described
Stock Delivery System (SDS) is prepared with Diosgenin
(25R)-Spirost-5-en-3.bet- a.-ol) as active ingredient; diosgenin is
a large (MW=414.6), difficulty soluble soy isoflavone:
9 Compound Function Amount (grams) Diosgenin Active 4.5 95%
Ethanol/Sec-butanol Primary Solvent 410 c.c. SDS Primary Delivery
90 c.c. Alpha lipoid (Thioctic) Acid Complexer 0.5 Methyl Sulfonyl
Methan Comlex Former 0.5 3,3'-Thiodipropionic Acid Complexer
0.2
[0214] A second lotion incorporating other soy isoflavanone
compounds is prepared as follows:
10 Compound Function Amount (grams) Genistein Active 5.0 Daidzein
Active 5.0 Biochanin A Active 5.0 Phosphatidyl Serine Complexer 25
c.c. SDS Primary Delivery 500 c.c.
[0215] In the above formula, daidzein is 4',7- dihydroxyisoflavone.
Biochanin is the 4'-methyl ether of genistein
(5,7-dihydroxy-3-(4-hydroxp- henyl)-4H-1 bensopryran-4-one;
4',5,7-trihydroxyisoflavone.
[0216] These two formulations when used in combination, are
expected to be useful in the treatment of prostate cancer.
EXAMPLE 2
[0217] A hormone replacement therapy formulation, especially useful
in the treatment of Benign Prostatic Hyperplasia (BPH) using a
lower concentration of soy isoflavanones, than in the formulations
of Example 1, again in the form of a lotion, is prepared with the
following ingredients:
11 Compound Function Amount (grams) SDS Primary Delivery 500 c.c.
Diosgenin Active 2.5 Dehydroepiandosterone Skin Stabilizer/Active
7.5 Pregnenolone acetate Skin Stabilizer/Active 1.25 Dopamine Tonic
0.1 Para-aminobenzoic Acid B Complex Former, 0.5 Skin Stabilizer
2-Diethylaminoethanol Solute Modifier 0.5 Ascorbyle Palmitate
Solvent Modifier 0.15
[0218] To enhance the cosmetic tonic properties of the above
formulation, various cosmetic additives can be added to the above
formula, for example, various plant extracts, such as, for example,
extracts of camomile, rosemary, rose hip, horsetail, in amounts of,
for example, 10 cc, 5 cc, 5 cc, and 5 cc, respectively.
EXAMPLE 3
[0219] A similar, but milder, formulation to that of example 2,
more suitable for a female cosmetic product is formulated as
follows:
12 Compound Function Amount (grams) SDS Primary Delivery System 300
Pregnenolone acetate Skin Stabilizer/Active 1.0 Diosgenin Active
0.6 Dehydroepiandosterone Skin Stabilizer/Active 0.6 Forskoli
(extract, 40%) 65 mg. 3-Hydroxy Tyramine Tonic 50 mg. (Dopamine)
Camomile Extract Tonic 5.0 cc Ascorbyle Palmitate Solvent Modifier
0.3 Para-aminobenzoic acid B Complex Factor, Skin 0.5 Stabilizer
2-Diethylaminoethanol Solute Modifier 0.5 Horsetail Extract Tonic
0.5 3,3'-Thiodiproprionic acid Solute Modifier 0.075 Methyl
Sulfonyl Methane Solvent Modifier 0.5
EXAMPLE 4
[0220] The following female tonic preparation is prepared using the
invention Stock Delivery System (SDS) to which pregnenolone acetate
(PA) (3 mg/cc) is added:
13 Compound Function Amount SDS + PA Primary Delivery System 100 cc
+ 0.3 g Dehydroepiandosterone Skin Stabilizer/Active 1.25 g
Diosgenin Active 0.1 g Hypericum Tonic 30.0 cc Camomile Extract
Tonic 10.0 cc Rosemary Extract Tonic 10.0 cc Rosehip Extract Tonic
10.0 cc Hosetail Extract Tonic 10.0 cc Pregnenolone acetate Tonic
100 mg
EXAMPLE 5
[0221] A tonic formulation, suitable for an over-the-counter
hormonal product is produced with the following ingredients:
14 Compound Function Amount (grams) SDS with Primary Delivery
System 100 cc Pregnenolone acetate Active 0.3 (3 mg/cc)
Dehydroepiandosterone Skin Stabilizer/Active 1.25 Diosgenin Active
0.1 Hypericum Tonic 30 cc Camomile Extract Tonic 10 cc Rosemary
Extract Tonic 10 cc Rosehip Extract Tonic 10 cc Horsetail Extract
Tonic 10 cc Pregnenolone acetate Tonic 100 mg
EXAMPLE 6
[0222] Another tonic formulation is prepared with the following
ingredients:
15 Compound Function Amount SDS Primary Delivery System 200 cc
Hypericum Tonic 20.0 cc Glycyrrhiza Tonic 20.0 cc NADH Tonic 6.0 mg
Dopamine Tonic 1.0 mg Diosgenin Active 400 mg Pregnenolone acetate
Tonic 50 mg Camomile Extract Tonic 5.0 cc Rosemary Extract Tonic
1.0 cc Rosehip Extract Tonic 1.0 cc
EXAMPLE 7
[0223] The following hormone therapy formulation, designed for
female hormone replacement therapy, is prepared:
16 Compound Function Amount SDS+ Primary Delivery 100 cc Ferulic
Acid+ Complexer 2.0 g Estriol Active 0.6 g Dehydroepi-andosterone
Skin Stabilizer/Active 4.0 g Progesterone Tonic 4.0 g Pregnenolone
Acetate Tonic 0.6 g Testosterone Tonic 5.0 g hormones, e.g.,
Therapeutic element per Triestrogens
[0224] In the above formulation 0.5 grams of pregnenolone may be
used in place of the 0.6 g of pregnenolone acetate.
EXAMPLE 8
[0225] This example shows the preparation of an aqueous emulsion
topical delivery system (OTC) according to the invention for the
topical administration of the antibacterial Quaternium 28 (dimethyl
benzethonium chloride):
17 Compound Function Amount (wt. %) Quaternium28 Active 0.25 Adogen
.RTM. DHT.sup.1 Solvent Modifier 4.0 Lauricidin .RTM. Skin
desensitizer; 6.0 anti-inflammatory Methylsulfonyl- Solvent
Modifier 2.4 methane Ascorbyl Palmitate Solute Modifier 0.3 Vitamin
E Acetate Solvent Modifier 0.4 Lemon Oil (Cold Solvent Modifier 0.8
pressed, highest food grade) D-Panethenol Solvent Modifier 0.1
Allantoin Skin Stabilizer 0.3 Emu Oil Natural Oil 1.0 Cetyl
Palmitate Skin Stabilizer 0.25 Varisoft .RTM. 475 Solvent Modifier
4.0 Decanoic Acid Solvent Modifier 0.3 Triglyceride Water (DI)
Solvent 79.9
[0226] The above ingredients are formulated into an emulsion in
which the Varisoft, Adogen, Methylsulfonylmethane and Quaternium
compounds are present in the aqueous phase; and Lauricidin,
Ascorbyl palmitate, Ceyl palpitate, Vitamin E acetate, D-panthenol,
allantoin, Emu Oil and decanoic acid triglyceride are present in
the organic phase. The lemon oil is present at the interfaces of
the oily and aqueous phases.
[0227] .sup.1dihydrogenated tallow dimethyl ammonium chloride; may
also function as active ingredient, e.g., as a pain reliever, and
also as an anti-irritant.
[0228] The formulation may be prepared, for example, by combining
the water soluble ingredients and heating to about 60.degree. C.
Separately, the organic phase ingredients are combined and heated
to about 63.degree. C. with care being taken to avoid temperatures
about 70.degree. C., preferably, not exceeding about 65.degree. C.
Thereafter, the above water soluble and oil soluble components are
combined by adding the oil phase to the water phase and mixed in a
closed, heated vessel. Water is added to achieve a workable
consistency at which time mixing is continued with addition of the
remaining water and after cooling to about 50.degree. C. the lemon
oil is added. Mixing is continued for about 1 hour at high, e.g.,
1,200 rpm, speed, while continuing to cool. The vessel should,
preferably, remain in the closed condition during this cooling. The
cooling is conveniently accomplished using a cooling jacket on the
outside of the mixing vessel. When the mixture cools to about
35.degree. C. it is ready to be transferred to smaller containers
for subsequent handling or transfer.
[0229] The mixture becomes quite viscous below about 50.degree. C.
so appropriate transfer procedures should be adopted.
[0230] For best results, during the mixing steps, the contents in
the mixing vessel should be maintained at a level such that the
depth of any vortex formed during mixing is about 25% of the depth
in the vessel. As expected, the vortex depth will tend to increase
as the temperature decreases and thickening increases. The mixing
should be accomplished under conditions which avoid aeration.
EXAMPLE 9
[0231] This example describes the results of an animal (mouse)
study performed at St. Bartholomew's and The Royal London School of
Medicine and Dentistry, Department of Experimental Pathology, to
establish the efficacy of the topical delivery system, based on the
Stock Delivery System of this invention for transdermal delivery of
Cystamine (2,2'-dithiobisethanamine). A Murine Chronic
Granulomatous Air-Pouch Model was used for evaluation of the
delivery of the drug with SDS versus a control vehicle alone;
control vehicle plus drug; and SDS alone.
[0232] The Air-Pouch Model was selected as an attractive method for
studying inflammatory processes since rodent air pouch has been
shown to develop into a structure resembling the synovium of
diarthrodial joints and in view of ease of induction and
possibilities or serial sampling of fluid and tissue. In addition,
the air pouch has been developed further in mice for use in the
examination of the angiogenic response. The murine chronic
granulomatous air pouch is advantageous for study in view of the
ease of therapeutic manipulation in this species used and, further,
the development of the vasculature may be readily assessed by dye
incorporation assays. The metabolic responses of the lining cells
of the murine air pouch was assessed for comparison to the enzyme
induction seen in rheumatoid synoviocytes, and the model
subsequently used for assessing the potential of varying agents to
modulate the angiogenic response.
[0233] In this study, 1 milligram (mg) of cystamine was added to
0.5 cc of Standard Stock Solution (SDS) as previously described, or
to a control vehicle (aqueous isopropanol). In each case, the
active ingredient (cystamine) was administered in an amount of 30
mg per kilogram of body weight.
[0234] Mice (TO or BALB/c, for hormone studies, 30.+-.5 g) were
lightly anaesthetized with halothane. Three milliliters of air were
injected subcutaneously into the scruff of the neck using a 25 G
needle. The shape of the air pouch was controlled by manipulation
during inflation. One day later, 0.5 ml Freund's complete adjuvant
supplemented with 0.1% croton oil was injected into the air pouch
using a 21 G needle. Animals were killed at various time points for
assessment of pouch vascularity, histology and cleared air pouch
preparations. Vascularity was assessed by a modified form (see
Kimuar et al, [need citation]1986) of the Carmine Red Vascular
Casting technique. Mice were anesthetized using hypnorm/hypnovel
and kept warm on a heated box at 40.degree. C. for 10 minutes. One
millitier (1 ml) of 25% carmine red dye in 10% gelatin at
40.degree. C. was injected into the tail vein of each mouse.
Cadavers were chilled at 4.degree. C. for 4 hours and the
granulomas dissected free. Granulomas were weighted after drying in
an oven for 2 days at 56.degree. C. The dried granulomas were
digested for 24 hours at 56.degree. C. in 0.9 ml of digestive
solution (12 units ml-.sup.1 papain in 0.05M phosphate buffer, pH
7.0, supplemented with 0.33 g/liter N-acetyl cysteine) for
cotton-wrapped cartilage granulomas and 9 ml for air pouch
granulomas. A volume of 0.1 ml or 1 mol of 4M sodium hydroxide (for
each type of granuloma, respectively) was mixed well with each
digest. The digests were centrifuged at 200 g for 10 minutes and
filtered through a 0.22 .mu.m nitrocellulose disposable filter. The
dry content was measured spectrophotometrically at 490 nm against a
standard curve of dye from 1-100 .mu.g/ml. Digests were diluted as
appropriate to bring them onto the standard curve and blanked
against non- injected control granulomas treated in the same
way.
[0235] Results are expressed, below, as .mu.g carmine red dye per
mg dry tissue mass. In some cases, exudate was recovered from the
air pouches at termination, 5M sodium hydroxide added to give a
final concentration of 0.5M sodium hydroxide and processed as above
to determine carmine content.
18 Delivery System Dry Weight of Granuloma (mg) Control vehicle
(CV) 0.114 .+-. 0.113 CV + cystamine 0.115 .+-. 0.008 SDS 0.1334
.+-. 0.009 SDS + cystamine 0.082 .+-. 0.006* *p = 0.291 SDS/(SDS +
cystamine) **p = 0.0003
[0236] From the above results, namely, a decrease in dry weight of
the granuloma, it is apparent that the SDS is highly effective as a
delivery vehicle which, in fact, converts the normally
sub-effective dose (30 ms/kg) of cystamine to an effectively
dose.
EXAMPLE 10
[0237] This example is for an aqueous based weight reducing formula
in which caffeine and the conjugated isomer of lineolic acid (CLA)
are used as the primary active agents.
[0238] The formulation was prepared without use of modeling
software.
19 Amount Ingredient Function (parts by weight) Caffeine Active
0.05 CLA Active 1.2 Aescin Solute Modifier 0.1 Pyridoxal-5-
Active/Vitamin 0.001 Phosphate (P-5-P) Liquorice Active Hormone
0.05 (20% glycyrrhizic Acid) Modulator Ephedrine Solute Modifier
0.5 Active/CNS Stimulant Theophilline Solute Modifier + Active/ 1.5
CNS Stimulant Olive Oil Solvent Modifier 4.0 Carnitine Solute
Modifier 0.1 MSM Solvent Modifier 2.0 Ascorbic Palmitate Solvent
Modifier 0.15 Lemon Oil Solvent Modifier 0.8 Alpha-lipoid acid
Solute Modifier 0.2 Lauricidin Skin Stabilizer 1.0 Adogen DHT
Solvent Modifier 4.65 Allantoin Skin Stabilizer 0.3 Vitamin B
acetate Skin Stabilizer 0.25 Dexpathenol Solvent Modifier 2.0 Water
Primary Solvent
[0239] The above formulation is designed for patients with severe
chronic obesity with cardiac complications. Therefore, forskolin is
not included in the formula in view of its cardiotonic effects
which, although only short-lived, is considered to present an
unnecessary risk. However, under appropriate circumstances
forskolin or equivalent may be added to the formulation with
expected improvement in speed of absorption and total uptake. In
addition, by more closely balancing moles-van der Waals forces to
within about 15% or less further improvements in the penetration
and performance characteristics would be achieved.
EXAMPLE 11
[0240] This example is for a pain treating composition, formulated
as an ointment.
20 Ingredient Amount (parts by weight) Merguard 0.125 Verisoft 475
3.6 Adogen DHT 3.2 Lauricidin 6.0 MSM 2.4 Ascorbic Palmitate 0.3
Vitamin E Acetate 0.4 Lemon Oil 0.8 Dexpanathenol 0.1 Allantoin 0.7
Olive Oil 1.0 Cetyl Palmitate 0.25 Dimethyl Benezethonium 0.25
Chloride Decanoic Acid 0.7 Triglyceride Sorbitan Palmitate 0.7
Water 5.225
[0241] The sum of the total system moles-van der Waals forces is
0.598 while for the total system less active agent (Varisoft 475)
sum of the moles-van der Waals forces is 0.516.
EXAMPLE 12
[0242] The following composition is an aqueous cream formulation
designed for promoting cellulite removal.
21 Ingredient Amount (parts by weight) CLA 0.3 Aescin 0.1 P-5-P
0.001 Liquorice (20%) 0.05 Ephedrine 0.5 Theophilline 1.5 Olive Oil
2.0 Carnitine 0.3 MSM 2.0 Ascorbic Palmitate 0.015 Lemon Oil 0.8
Alpha lipoid acid 0.2 Lauricidin 2.0 Adogen DHT 2.0 Allantoin 0.3
Vitamin E acetate 0.25 Dexpanthenol 2.0 Propylene Glycol 2.0
Water
[0243] The difference between the moles-van der Waals forces of the
carrier/solvent system (0.506) and the total system
(carrier/solvent plus active ingredient--therophilline) (0.552) is
about 8.33%.
EXAMPLE 13
[0244] This example describes the results of an in vitro trial
based on the stock delivery system of this invention, for
transdermal delivery of morphine (as morphine sulfate), in a Franz
Diffusion Cell model.
[0245] Evaluation of Morphine Formulation
[0246] This morphine formulation is designed as a therapeutical
product for cancer pain relief.
[0247] Presently, transdermal formulations developed for the
purpose of cancer pain relief have not yet been found to be
successful for practical use. One reason, is that the level of
morphine required to show an analgesic effect is very high, in the
order of 70 mg/day (in the case of applying to a 100 cm.sup.2 area,
a transdermal absorption rate of 27 .mu.g/hr/cm.sub.2 is necessary)
if an absorption enhancer strong enough to have such a high level
of morphine absorbed transdermally is used, it is inevitable that
serious skin irritation will result.
[0248] The evaluation of the subject formulation was performed in
vitro with skin taken from a hairless rat. Since the barrier
ability of the stratum corneum does not differ between in vitro and
in vitvo status, transdermal absorption may be correlated evaluated
with the in vitro skin permeation test.
[0249] Experiment
[0250] 2 kinds of SDS vehicles were used:
[0251] SDS-L for topical use--lotion (see Table 8);
[0252] SDS-S for systemic use--lotion (see Table 9).
[0253] The morphine sulfate was supplied by Sankyo Pharmaceuticals,
Japan.
22 TABLE 8 Compound Mole Wt. Amt (g)/100 ml Morphine Sulfate 668.77
0.25 SDS-L MSM 94.13 2 Ethanol 46.07 56.881 Water 18 2.862
Propylene Glycol 76.01 42.131 Limonene 136.24 0.102 Vit E 430.17
0.051 Dexpanthenol 205.25 0.053 MSM 94.13 0.102 Lauriciden 181.97
0.254 Oxindole 2.95 0.003 Thioproprionic Acid 178.21 0.051
Forskolin 4.10 0.010
[0254]
23 TABLE 9 Compound Mole Wt. Amt (g)/100 ml Morphine Sulphate
668.77 0.25 SDS-S Ethanol 46.07 57.243 Acetone 58.08 5.0 Propylene
Glycol 76.01 42.131 Limonene 136.24 0.102 Vit E 430.17 0.051
Dexpanthenol 205.25 0.053 MSM 94.13 0.102 Lauriciden 181.97 0.254
Oxindole 295 0.003 Thioproprionic acid 178.21 0.051 Forskolin 4.10
0.010 Balancing Components ATP 507.17 0.25 Limonene 136.24 1.0 DMAE
89.14 1.0 Benzyl Alcohol 108.44 0.5 MSM 94.13 3.0
[0255] The standard stock solution, SDS-L, is not optimized for
system perfusion. However, for the systemic stock solution, SDS-S,
the additional MSM, additional limonene, DMAE and benzyl alcohol
are added to the solution to balance the formula as previously
described. Thus, the sum of the products van der Waals-moles for
the ingredients of SDS-S (namely, ethanol, acetone, propylene
glycol, Vitamin E, dexpanthenol, methylsulfonylmethane (MSM),
lauriciden, oxindole, thioproprionic acid, and Forskolin) is a
4.742, whereas the sum of the products VDW-moles for the final
formula (including morphine sulfate, additional MSM, additional
limonene, dimethylaminoethanol (DMAE), and benzyl alcohol) is a
4.861, a difference of only about 2.44%; additional limonene,
dimethylaminoethanol (DMAE), and benzyl alcohol) is 4.861, a
difference of only about 2.44%.
[0256] Skin Permeation Test
[0257] A vertical standing static type Franz Cell is employed. The
receptor phase is maintained at 37.degree. C. by circulating
uniformly heated water.
[0258] Skin is taken from the abdomen of a hairless rat, male, 12
weeks of age, purchased from Charles River Laboratories, and the
skin is stored for two weeks at -60.degree.. Just before use the
skin is gently thawed to room temperature and then cut into
circular shapes with a diameter of 3.5 cm and set into the Franz
Cell device.
[0259] The topical and systemic preparations are prepared by adding
28 mg of morphine sulfate to 10 ml each of SDS-L and SDS-S while
stirring at room temperature until the morphine sulfate is
completely dissolved and allowing the mixture to stand overnight,
while tightly sealed.
[0260] In order to compare effectiveness of the formulations as a
lotion and as a patch, the evaluations are made on two kinds of
applications: open condition, which mimics the application of a
lotion formulation and, closed condition, which mimics the
application of a patch formulation, as follows:
(i) Open Condition
[0261] At the beginning of the skin permeation test, 1 ml of the
morphine sulfate combined with SDS-L or morphine sulfate combined
with SDS-S is placed in the Donor Chamber of the Franz Cell. Air is
introduced for 10 minutes by a drier to volatilize the volatile
components in the vehicle. The Donor chamber is kept open until the
completion of the test.
(ii) Closed Condition
[0262] At the beginning of the skin permeation test, 1 ml each of
the morphine sulfate combined with SDS-L or morphine sulfate
combined with SDS-S is placed in the Donor chamber of the Franz
Cell. The Donor chamber is kept completely sealed until the
completion of the test.
[0263] Isontonic phosphate buffer, pH 7.2, consisting of 0.033 mM
sodium phosphate, 7.4% NaCl and 1% NaN.sub.3, (preservative) is
used as the receptor solution.
[0264] At each sampling time, established beforehand, 1.8 ml of the
solution in the receptor chamber is sampled, and the same volume of
receptor solution is added to the receptor chamber.
[0265] The concentration of morphine sulfate in each receptor
solution sampled is determined quantitatively by HPLC.
[0266] Based on the morphine sulfate concentration in the receptor
solution obtained as above, the amount of morphine sulfate
permeated per 1 cm.sup.2 of skin is cumulatively calculated, then
plotted against each sampling time. On the resulting skin
permeation profiles, the region where there is a linear relation
between the permeated morphine sulfate concentrations and the
sampling times is chosen. Then the linear equation that best fit
the region is determined by the least squares method. The
"permeation flux" is obtained from the slope and the "lag time"
from the time-axis intercept. The tests are repeated three times
and the average and standard deviation (SD) of the "permeation
flux" and the "lag time" are calculated.
Results
1. pH Values or Morphine Sulfate Combined with SDS-L and Morphine
Sulfate Combined with SDS-S
[0267] The pH values of vehicle combined with morphine sulfate (at
2.6 mg morphine sulfate/ml) was 6.14 for SDS-L and 5.77 for SDS-S,
respectively. Both formulations are non-toxic to the skin.
2. Volatility of Solvent under Open Conditions
[0268] Approximately half the volume of the solvent remained (not
volatized) after ventilation for 10 minutes with the drier. After
extending the test for 29 hours, about {fraction (1/10)} volume of
the solvent still remained in the donor cell.
3. Skin Permeation of the Morphine Sulfate from the Stock
Solution
[0269] Tables 10 and 13 and FIGS. 1-4 show the cumulative permeated
amount of morphine sulfate per 1 cm.sup.2 of hairless rat skin over
time. Table 14 shows the permeation of flux and lag time of
morphine sulfate obtained from the permeation profiles in FIG. 1.
For both SDS-L and SDS-S morphine sulfate is detected in the
receptor solution after 6 hours. Thereafter, the permeation flux is
approximately twice as fast in SDS-S than in SDS-L. In the case of
SDS-L, there is little or no difference in the permeation flux or
the lag time between the open conditions and the closed conditions.
In the case of SDS-S, there is also little or no difference in the
flux or lag time between open and closed conditions.
24TABLE 10 Amount of morphine sulfate through 1 cm.sup.2 of
hairless rat skin from SDS-L (open condition) Amount of morphine
sulfate through 1 cm.sup.2 of hairless rat skin (ug/cm.sup.2) Time
(hr) s-1 s-2 s-3 mean sd.sup.1) 0 0 0 0 0 0 3 0 0 0 0 0 6 0 0 0 0 0
22 118 6 8 44 64 26 373 44 48 155 189 29 564 141 119 275 251
.sup.1)standard deviation
[0270]
25TABLE 11 Amount of morphine sulfate through 1 cm.sup.2 of
hairless rat skin from SDS-L (closed condition) Amount of morphine
sulfate through 1 cm.sup.2 of hairless rat skin (ug/cm.sup.2) Time
(hr) s-1 s-2 s-3 mean sd.sup.1) 0 0 0 0 0 0 3 0 0 0 0 0 6 0 0 0 0 0
22 6 22 7 12 9 26 40 179 158 126 75 29 158 327 324 270 97
.sup.1)standard deviation
[0271]
26TABLE 12 Amount of morphine sulfate through 1 cm.sup.2 of
hairless rat skin from SDS-S (open condition) Amount of morphine
sulfate through 1 cm.sup.2 of hairless rat skin (ug/cm.sup.2) Time
(hr) s-1 s-2 s-3 mean sd.sup.1) 0 0 0 0 0 0 3 0 0 0 0 0 6 0 0 0 0 0
22 67 865 125 352 445 26 290 1140 447 626 452 29 464 1263 694 807
412 .sup.1)standard deviation
[0272]
27TABLE 13 Amount of morphine sulfate through 1 cm.sup.2 of
hairless rat skin from SDS-S (closed condition) Amount of morphine
sulfate through 1 cm.sup.2 of hairless rat skin (ug/cm.sup.2) Time
(hr) s-1 s-2 s-3 mean sd.sup.1) 0 0 0 0 0 0 3 0 0 0 0 0 6 0 0 0 0 0
22 717 599 1091 802 257 26 1040 940 1256 1079 162 29 1256 1112 1375
1248 132 .sup.1)standard deviation
[0273]
28TABLE 14 Permeation flux and lag time of morphine sulphate from
SDS-L or SDS-S through hairless rat skin formulation application
method flux(g/hr/cm.sup.2) lag time (hr) MS-1 open 33.+-. 21 .+-. 1
closed 36.+-. 22 .+-. 0 MS-2 open 65.+-. 16 .+-. 8 closed 64.+-. 7
.+-. 10
EXAMPLE 14
[0274] This example describes the result of an animal (hairless
rat) study performed to further establish the efficacy of the
topical delivery system, based on the stock delivery system of this
invention for transdermal delivery of morphine (mol. Wt. 285.34)
and also for acyclovir (mol. Wt. 225.21) and testosterone (mol. Wt.
288.43). The acyclovir and testosterone formulations are shown in
Tables 15 and 16, respectively. The morphine formulation is shown
in Table 9 above. A pilot trial is performed on three hairless
rats, during which a baseline blood sample is drawn, then 1 ml of
the topical delivery system containing a titrated dose of each of
the three test drugs is administered to each of the rats. Sample
are harvested at 30 and 60 minutes. The results are as follows:
29 Medicament Dose in 1 ml Baseline 30 minutes 60 minutes Morphine
2.5 mg 0 Ins. Sample 45 nmol/L Testosterone 5 mg 165 1,552 ng/dl
1600/dl Acyclovir 0
[0275] In view of these encouraging results a full-scale protocol
trial is performed on 15 hairless rats, divided into three groups
of five rats each. One group is dosed with the morphine formulation
of Table 10, one with the testosterone formulation of Table 11 and
one with the acylovir formulation of Table 12. Samples for the
morphine and acyclovir groups are taken at 30 minutes, 60 minutes
and 120 minutes. Samples from the testosterone group are taken at
Baseline -0 minutes, 30 minutes and 60 minutes. The results are as
follows:
30 Medicament Dose in 1 ml Baseline 30 minutes 60 minutes Morphine
2.5 mg 0 nmol/L nmol/L Acyclovir 0 ng/dl ng/dl Testosterone 5 mg
165 ng/dl ng/dl
[0276] Testosterone levels are increased 10-fold in one hour. A 2.5
mg dose of morphine, a dose which would be considered insufficient
to accomplish a therapeutic outcome if dosed intravenously,
provides blood levels equivalent to a 10 mg IV dose. Further,
morphine is considered extremely difficult to deliver transdermally
due to its highly lipophilic character.
[0277] The kinetic outcomes for all three molecules would be
sufficient to accomplish therapeutic doses in human beings.
31TABLE 15 Acyclovir Formulation Compound Mole Wt. Amt/100 ml
Acyclovir 225.09 MSM 94.13 3 5 SDS VitE 430.17 0.051 Despanthenol
205.25 0.053 MSM 94.13 0.10 Lauriciden 181.97 0.25 Oxindole 295
0.003 Forskoline 410 0.010
[0278] The sum of moles-van der Waals forces for the SDS components
is 0.0252 while the sum of moles-van der Waals forces for the SDS
plus acyclovir and additional MSM is 0.0353.
32TABLE 16 Testosterone Formulation Compound Mole Wt. Amt./100 ml
Testosterone 288.4 5.0 Ethanol 46.07 54.381 Water 18 2.862
Propylene Glycol 76.01 42.131 limonene 136.24 0.102 VitE 430.17
0.051 Dexpanthenol 205.25 0.053 MSM 94.13 0.102 Lauriciden 181.97
0.254 Oxindole alkaloid 295 0.003 Forskolin 410 0.010
[0279] In order to determine the transdermal absorption of
testosterone from this formulation, the formulation is applied to
rat skin (n=6) and the amount of absorbed through the skin is
measured at 0, 30 and 60 minutes. The results obtained are shown in
the following Table 17.
33TABLE 17 Testosterone absorption through the skin Plasma
testosterone, ng/gl Time Rat 1 Rat 2 Rat 3 Rat 4 Rat 5 Rat 6 Mean
Median 0 171 50 211 229 366 165 199 191 30 815 152 668 893 1577
1552 943 854 60 542 222 553 1321 2137 >1600 1062 937
EXAMPLE 15
[0280] The following lotion for transdermal delivery of male
hormones is prepared.
34 Compound Mole Wt. Amt/100 ml DHEA 288.4 1231 Diosgenin 414.6
0.115 Androstenedione 286.4 3.007 Ethanol 46.07 70.0 Acetone 58.08
Water 18 2.95 Propylene Glycol 76.01 22.0 limonene 136.24 0.10 VitE
430.17 0.06 Dexpanthenol 205.25 0.06 MSM 94.13 2.0 Lauriciden
181.97 0.20 Oxindole 295 0.01 Thioproprionic acid 178.21 Forskolin
4.10 0.04 Indole 3-Carbinol Rosemary
EXAMPLE 16
[0281] This example is directed to a formulation for transdermal
delivery of human growth hormone (HGH) (MW=20,000) using modified
form of the standard stock delivery system according to this
invention:
35 Amt/100 ml HGH 0.20 Cyclodextrin 5.0 MSM 1.5 Vitamin E 0.1
Dexpanthenol 0.055 Phytantriol 0.025 Oxindole 0.15 Forskolin 0.50
Tween 80 0.924 Ceterath 20 1.5 Guaifenensin 0.6 Inositol 0.6
Propylene Glycol 100.0 Water 10.0
EXAMPLE 17
[0282] This example illustrates modification of the proportions of
the active ingredients and delivery system to match the
physicochemical properties (here, van der Waals forces) of the
active ingredients and carrier systems, to maximize effectiveness
of the transdermal delivery of the active ingredients. In this
case, the active ingredients, including the combination of
Lorazepam and Ibuprofen, provide an anxiolytic or muscle relaxant
treatment.
36 Formula 17-A Formula 17-B Ingredient Amt/100 ml Amt/100 ml
Flubiprofen 1.00 0.75 Diazepam 0.5 0.5 Ibuprofen 0.8 0.8 Lorazepam
0.3 0.3 MSM 4.0 4.0 Ethanol 56.9 56.9 Water 18.0 18.0 Propylene
Glycol 42.1 42.1 Limonene 0.10 0.10 Vitamin E 0.05 0.05
Dexpanthenol 0.05 0.05 MSM 0.10 0.10 Lauriciden 0.25 0.25 Oxindole
0.003 0.003 Thioproprionic Acid 0.05 0.05 Forskolin 0.01 0.01
Vinpocetine 0.01 0.01 Resveratrol 0.02 0.02 Emodin 0.01 0.01
Cyclobenzaprin HCl 0.50 0.80 Inositol 0.60 0.60 Guaifenensin 0.60
0.60 Prozac 1.0 0.5 GABA 1.0 1.0
[0283] For formula 17-A the sum of the moles-van der Waals (VDW)
for delivery system is 2.892 while for the delivery system and
activities, the sum is 5.021. However, for formula 17-B the sum of
moles-VDW is 2.838 for delivery system and 2.9687 for delivery
system plus actives.
REFERENCES
[0284] 1. T. K. Ghosh, et al., Methods of Enchancement of
Transdermal Drug Delivery, Parts I, Ida* IIb, Chemical Permeation
Enhancers, Pharm, Tech. 17 (3): 72-98m 17 (4): 62-89m 17 (5): 68-76
(1993).
[0285] 2. Crouch, James E., Functional Human, Anatomy, Lea &
Fibiger, LOCCN 65-12968, Chapter 6, pp. 88-97, 1965.
[0286] 3. K. Tojo, Random Brick Model for Drug Transport Across
Stratum Corneum, J. Pharm, Sci., 76:889-891
[0287] 4. S. D. Roy, Preformulation Aspects of Transdermal Delivery
Systems, In: Transdermal and Topical Drug Delivery Systems, Eds. T.
K. Ghosh, W. R. Pfister, S. I. Yum, Interpharm Press, Inc., Buffalo
Grove, Ill. 1997.
[0288] 5. K. Gjesdal, et al., Transdermal Nitrate Therapy:
Bioavailability During Exercise Increase Transiently after the
Daily Change of the Patch, Brit. J. Clin. Pharmacol. 31:560-562
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[0289] 6. K. Tojo, The Predication of Transdermal Permeation:
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[0290] 7. I. Diez, et al., A Comparative In Vitro Study of
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Sci. 80:931-934 (1991)
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with Transdermal Drug Deliery Systems, Parts I & II: Selection
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(10) :56-60.
[0292] 9. C. D. Vaughn, Using Solubility Parameters in Cosmetic
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[0293] 10. J. W. Streilein, In: Immune Mechanisms in Cutaneous
Diseases, Ed. D. A. Norris, Marcel Dekker, Inc., New York, pp.
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[0294] 11. J. Ademola, et al., Safety Assessment of Transdermal and
Topical Dermatological Products In: Transdermal and Topical Drug
Delivery Systems, Eds. T. K. Ghosh, et al., Interpharm Press, Inc.,
Buffalo Grove, Ill., (1997).
[0295] 12. P. Liu, et al., Quantitiative Evaluation of Ethanol
Effects on Diffision and Metabolism of .beta.-Estradiol in Hairless
Mouse Skin, Pharm. Res. 8:865-872 (1991).
[0296] 13. Lubert Styer, Biochemistry, 2n Edition, Chapter 35, pp.
839-858, W. H. Freeman, CO., New York, (1981).
[0297] 14. Kenneth B. Seamon, et al., Foskolin: Unique Diterpene
Activator of, Adenylate Cyclase in Membranes and Intact Cells;
PNAS, vol. 78, no. 6, pp. 3363-3367 (June 1981).
[0298] 15. Hermann P. T. Ammon, et al., Forskolin: From Ayurvedic
Remedy to a Moder Agent; Planta Medica, pp. 473-476 (1985).
* * * * *